Is KRT86 p.Pro76Ala (c.226C>G) pathogenic?

KRT86 p.Pro76Ala (c.226C>G) is classified Uncertain significance in KRT86 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0935); Ultra-rare (popmax 0.0486%, afr); Associated with Inborn genetic diseases.

What condition is associated with KRT86 p.Pro76Ala (c.226C>G)?

KRT86 p.Pro76Ala (c.226C>G) is associated with Inborn genetic diseases (ClinVar).

How common is KRT86 p.Pro76Ala (c.226C>G) in the general population?

KRT86 p.Pro76Ala (c.226C>G) is ultra-rare (popmax 0.0486%, afr) (gnomAD).

What do computational predictors say about KRT86 p.Pro76Ala (c.226C>G)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

KRT86 p.Pro76Ala

c.226C>G · rs773655908 · VCV2407201

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0486%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -4.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 363 bp · p 0.52 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0486% African / African-American · 34/69,964 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00245% 37/1,512,348 alleles · ultra-rare exomes 16/1,367,338 · genomes 21/145,010 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0486%	2,058
Remaining individualsnot grpmax-eligible	0.00511%	19,583

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KRT86
Protein: p.Pro76Ala
Coding: c.226C>G
MANE Select: NM_001320198
dbSNP: rs773655908
Type: single nucleotide variant
Location: chr12:52302142 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.50
Residue 76: the 'head' region

Full KRT86 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT86 p.Ala293Asp Uncertain significance ★★ ⚠ same condition
KRT86 p.Ala218Thr Uncertain significance ★ ⚠ same condition
KRT86 p.Ala360Ser Uncertain significance ★ ⚠ same condition
KRT86 p.Ala383Asp Uncertain significance ★ ⚠ same condition
KRT86 p.Ala404Thr Uncertain significance ★ ⚠ same condition
KRT86 p.Ala446Asp Uncertain significance ★ ⚠ same condition
KRT86 p.Arg21Pro Uncertain significance ★ ⚠ same condition
KRT86 p.Arg221His Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/krt86-p-pro76ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown