Is KRT6A p.Val523Phe (c.1567G>T) pathogenic?

KRT6A p.Val523Phe (c.1567G>T) is classified Benign in KRT6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0773); Common (popmax 21.7%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about KRT6A p.Val523Phe (c.1567G>T)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

KRT6A p.Val523Phe

Q: How common is KRT6A p.Val523Phe (c.1567G>T) in the general population?

KRT6A p.Val523Phe (c.1567G>T) is common (popmax 21.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1567G>T · rs62617088 · VCV1601017

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.8
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	8.298	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.7% African / African-American · 16,246/75,016 alleles

Filtering AF 21.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.3%

Overall 2.04% 32,953/1,613,990 alleles · common exomes 22,025/1,461,684 · genomes 10,928/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	21.7%	5
Admixed American	7.62%	13
East Asian	3.94%	25
Middle Eastern	3.48%	29
Remaining individualsnot grpmax-eligible	2.72%	37
South Asian	1.86%	54
Ashkenazi Jewishnot grpmax-eligible	0.956%	105
European (non-Finnish)	0.545%	184
Amishnot grpmax-eligible	0.219%	456
Finnishnot grpmax-eligible	0.0687%	1,456

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: KRT6A
Protein: p.Val523Phe
Coding: c.1567G>T
MANE Select: NM_005554
dbSNP: rs62617088
Type: single nucleotide variant
Location: chr12:52487848 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 523: the 'tail' region

Full KRT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT6A p.Val523Ile Likely benign ★★ same residue
KRT6A c.1460-1G>C Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Arg164Cys Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Asn171Lys Pathogenic ★★ same type
KRT6A p.Asn171Ser Pathogenic ★★ same type
KRT6A p.Glu163Lys Pathogenic ★★ same type
KRT6A p.Glu472Lys Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Ile462Asn Pathogenic/Likely pathogenic ★★ same type

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/krt6a-p-val523phe (accessed [today's date]).

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