Is KRT6C p.Asp331His (c.991G>C) pathogenic?

KRT6C p.Asp331His (c.991G>C) is classified Uncertain significance in KRT6C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-13). AlphaMissense: likely pathogenic (0.7022); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRT6C p.Asp331His (c.991G>C)?

KRT6C p.Asp331His (c.991G>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6C p.Asp331His (c.991G>C) in the general population?

KRT6C p.Asp331His (c.991G>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about KRT6C p.Asp331His (c.991G>C)?

AlphaMissense predicts likely pathogenic (score 0.7022) — an in-silico prediction, not a clinical call.

KRT6C p.Asp331His

c.991G>C · rs760159262 · VCV2191222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7022 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7022	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -15.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.35	GERP 0.87, phastCons 0.81
Regional constraint	o/e 0.97	unconstrained · MANE · 3,104 bp · p 0.49 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00237% European (non-Finnish) · 28/1,180,038 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,614,088 alleles · very rare exomes 24/1,461,892 · genomes 5/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: KRT6C
Protein: p.Asp331His
Coding: c.991G>C
MANE Select: NM_173086
dbSNP: rs760159262
Type: single nucleotide variant
Location: chr12:52471218 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.63
Residue 331: the if rod domain; the 'linker 12' region

Full KRT6C 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

KRT6C p.Arg260Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg349Trp Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg466Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Glu479Lys Uncertain significance ★★ same condition
KRT6C p.Gly504Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly525Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly57Arg Uncertain significance ★★ ⚠ same condition
KRT6C p.Ile395Met 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/krt6c-p-asp331his (accessed [today's date]).

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