Is KRT6A p.Pro154Ala (c.460C>G) pathogenic?

KRT6A p.Pro154Ala (c.460C>G) is classified Benign in KRT6A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.6026); Rare (popmax 0.474%, nfe).

How common is KRT6A p.Pro154Ala (c.460C>G) in the general population?

KRT6A p.Pro154Ala (c.460C>G) is rare (popmax 0.474%, nfe) (gnomAD).

What do computational predictors say about KRT6A p.Pro154Ala (c.460C>G)?

AlphaMissense predicts likely pathogenic (score 0.6026) — an in-silico prediction, not a clinical call.

KRT6A p.Pro154Ala

c.460C>G · rs11836126 · VCV2643027

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6026 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.474%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6026	likely pathogenic
REVEL	0.722	pathogenic-leaning
SaProt	LLR -10.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	22.7	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 0.474% European (non-Finnish) · 5,595/1,179,974 alleles

Filtering AF 0.464% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.459%

Overall 0.394% 6,367/1,614,032 alleles · rare exomes 5,941/1,461,814 · genomes 426/152,218 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.659%	152
European (non-Finnish)grpmax	0.474%	211
Remaining individualsnot grpmax-eligible	0.326%	306
Middle Eastern	0.132%	757
Admixed American	0.085%	1,177
African / African-American	0.0693%	1,443
South Asian	0.0351%	2,845
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro154Ala
Coding: c.460C>G
MANE Select: NM_005554
dbSNP: rs11836126
Type: single nucleotide variant
Location: chr12:52492729 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 154: the 'head' region

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

Similar variants

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
KRT6A p.Leu170Phe 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-pro154ala (accessed [today's date]).

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