It should be noted that this weakness is only as big as it needs to be. The more Genre Savvy alchemists have circles on their clothing or tattooed on their body, making it even easier for them to use their powers than for Edward who still needs to clap his hands together.
But one small scratch on those circles, then those alchemists will lose their alchemy ability until they find a back up circle or repair it, whereas Ed's hand has to be destroyed to stop him from using alchemy. Good luck on that one unless you are Scar.
In addition, most alchemists who carry their transmutation circles around with them can only do specialized alchemy—Mustang can only create fire, Kimblee can only blow stuff up, etc. Alchemy without an array is far more versatile, to the point that Ed can actually cancel out others' alchemic reactions. His alchemy is only limited by his knowledge and creativity, which means that he and other alchemists who have seen the Truth have a massive advantage even over alchemists with array tattoos.
Clare, the protagonist of Claymore, seems to be completely immune to Awakening (even when she is deliberately trying to!), which threatens every other Claymore. The main reason for that is believed to be Jean's sacrifice to bring her back from the brink of Awakening before, which left Clare with a psychological block that prevents her from transforming, though this may also have something to do with her being only quarter-yoma.
In addition to physical deformities, the other Borners in the anime Canaan have to take regular shots of medication to avoid death from their virus-originated superpowers. The eponymous protagonist has neither of these problems (though her hair did go white because of them).
There is another character who received an internal and therefore invisible physical mutation. She however didn't seem to get any powers.
To clarify, the character in question had two appendixes as her mutation. Not exactly super-powered synthesia. It does bring up the question of if she'd still have to take the medication if she got them removed, too...
Rosario + Vampire: After a series of near-death instances, Tsukune gains vampire powers from various blood transfusions. Unlike the female lead Moka, this comes without the Weaksauce Weakness. He effectively has no weaknesses (well, other than the potential to go berserk and Crucifixes), which gives him an advantage.
In Bleach, mastering the Bankai can take a Shinigami as long as ten years. This is because, even though the Bankai is essentially only a bigger version of the Shikai, the amount of power can be 5 to 10 times greater and thus much more difficult to control. Enter The Hero, Ichigo, whose Bankai actually compresses his spiritual power giving him more speed and control.
Kill la Kill: Ryuko's Kamui Senketsu turns out to be the only non-malevolent life fiber.
Depending on the year/dimension/day-of-the-week: Power Girl is a kryptonian who is immune/resistant to kryptonite because she's really an alternate universe kryptonian.
To be clear, Kryptonians are only susceptible to kryptonite from their own universe. It varies with Power Girl because she was kind of sort of folded into the current universe but isn't from Krypton.
Superman of Earth-22 is not only immune to New Earth kryptonite but also his own due to a lifetime spent soaking up sunlight. All-Star Superman develops this immunity for basically the same reason but it leaves him with a progressive fatal condition. During the Bronze Age even the mainstream Superman got in on the act for a little while.
While most Kryptonians are susceptible to magic, Superboy-Prime ended up being altered just enough that being slugged by a lightning-infused Black Adam did zilch to him.
"Imaginary" stories depicting Kryptonian-human offspring tend to depict them as being half as powerful as their kryptonian parents but also half as weak to kryptonite.
Blade (the "Day Walker") is a half-vampire with "all of their strengths, and none of their weaknesses." The slogan is actually fibbing: he feels blood hunger but can ignore it, and he ages normally.
Sonja Blue is the heroine of a daywalker vampire hunter series.
Jane from The Iron Dragon's Daughter has this nice passive skill of being immune to regular defensive in-world charms, since they are helpless against human blood.
Bella doesn't suffer from the typical uncontrollable vampire hunger in Breaking Dawn.
The intentional creation of one of these by eugenic planning is the goal of the Bene Gesserit order in Dune: the Kwisatz Haderach, a man possessing the normally Gender Restricted Abilities of a Bene Gesserit sister, while also capable of accessing parts of the mind a woman could not.
Most of the human population in Codex Alera can use one or two types of elemental fury, which invariably leaves them vulnerable to other types. The exception are powerful noble families, particularly the High Lords, which generally have access to all six types of furies, making them incredibly powerful and without obvious weaknesses.
This is most prominent with Watercrafters, compared to Watercrafter-Metalcrafters. Watercrafting has a constant disadvantage (an empathic sense that cannot be shut off) and not just deficiencies in the furycrafting that can be exploited. Metalcrafting can compensate for that by artificially repressing the wielder's emotions.
In The Dresden Files, Outsiders, being literal aliens, have an immunity to magic which means that only the oldest, most experienced wizards have a chance of defeating them. The protagonist, despite being a relatively young wizard, can bypass this immunity instinctively to attack them effectively. This is because of a ritual his mother performed at his birth, making him a Starborn. It doesn't do him much good though, because 99% of the creatures he fights are from his own universe, and Outsiders are extremely difficult to fight even with this ability.
Eli Monpress in The Spirit Thief has the ability to simply talk to spirits and convince them to do his bidding, as opposed to the other wizards in the world who need to make pacts with spirits in order to access their power.
In The Magister Trilogy, all human magic is Cast from Lifespan. While this means that most witches must be very careful with their magic, because they have a very strictly finite amount, there exist a handful of men known as Magisters who deliberately burn up their own lifespan and latch onto someone else's. This makes them effectively immortal and thus grants near-infinite power. A Magister can only be killed if you catch them by surprise and kill them before they can defend or heal themselves with magic, or if you catch them during Transition, the few seconds between when one consort dies and when they bond another.
Downplayed in Planescape: Torment: The Nameless One is the only character capable of changing classes, meaning he can become a Fighter, Mage or Thief as the needs require, but unlike some of his companions cannot play a hybrid class, meaning his stats grow slower.
Alucard of the Castlevania series reaps many benefits from his status as a Dhampyr, such as resistance to sunlight and holy symbols along with the ability to survive without feeding on blood. However, he does play more fair than many other examples by logically being only half as powerful as a full-blooded vampire.
The main characters of Persona 3 and 4 are both special cases who can have multiple Personas, avoiding the set weaknesses of every other Persona user. In 4, while everyone else has to own up to their own darker thoughts, the main character doesn't have a hidden dark side to face.
Notably, this doesn't apply to the firsttwo games, where the characters gain their Personae in different fashion.
Much of Elizabeth's story in Persona 4 Arena revolves around her trying to learn more about the nature of this "Wild Card" ability that the P3 and P4 protagonists possess. She can already do pretty much anything, but even to her it remains something special and mysterious.
In the Fable series, the main character's bloodline is unique in that it results in heroes that can access all three disciplines (Strength, Skill, and Will), while most heroes are only able to access one.
In The World Ends with You, Neku is one of the few players who has access to multiple powers/pins (most of his partners just have one ability that they make use of, e.g. Shiki's ability to animate her stuffed animal).
In Deus Ex: Human Revolution, Adam Jenson turns out not to need the anti-rejection drug other cyborgs do (thus allowing him to avoid the side effects, as well as have fairly extensive upgrades). In a sidequest you can discover this was a result of experiments he was a part of as a child. His girlfriend reverse-engineering this trait is the breakthrough discovery she was about to announce to the world at the start of the game as well as what leads to the creation of JC and his brother in the original Deus Ex.
Generator Rex: In a world where every living thing is infected with nanomachines, Rex is one of the few people able to control them.
Bobo Haha. All the nanites did to him was make him smarter. This might not count, since he lacks any Lovecraftian Superpower that is typically dished out, but the monkey dodged all the downsides of being an EVO.
To elaborate, benders (people who can potentially manipulate fire, wind, water, or earth) are born with the ability to be control a single element meaning, an earthbender can never learn waterbending (for example). Though, as Iroh demonstrated, the styles of other bendersnote since each element is bent using different martial art stances and disciplines can have applications with benders of different elements. If used correctly of course. Which is yet another reason why the Avatar is so powerful given his or her collective knowledge can be used across all four elements.
In Worm, Contessa is one of two Thinkers on the planet whose powers aren't disrupted by other Thinkers, and the specific nature of her Combat Clairvoyance means that without this weakness she's essentially unbeatable. Unfortunately, the other is the Simurgh, who is immune to all precog and the apparent Big Bad.
Weld, as a parahuman made of living metal, is in the unique position of being immune both to powers that only work on metal and powers that only work on flesh.
Things like breeding, genetic engineering, medicine, and eventually Transhumanism are about stripping the Weaksauce from either ourselves or other living things we interact with.
Evolution is nature's way of countering or mitigating the weaknesses of lifeforms. However, it is undirected and settles for adequacy, which may cause weaknesses that can become far more crippling in future conditions. It's also REALLY slow for us multicellular organisms.
The advent of sexual reproduction was an important milestone in directing and accelerating this process for several reasons.