Is KRT6A p.Ala423= (c.1269C>T) pathogenic?

KRT6A p.Ala423= (c.1269C>T) is classified Benign/Likely benign in KRT6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). Rare (popmax 0.203%, amr).

How common is KRT6A p.Ala423= (c.1269C>T) in the general population?

KRT6A p.Ala423= (c.1269C>T) is rare (popmax 0.203%, amr) (gnomAD).

KRT6A p.Ala423=

c.1269C>T · rs145246640 · VCV2046243

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.203%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP 0.89
Overall
CADD	8.707	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.203% Admixed American · 122/59,996 alleles

Filtering AF 0.174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.163%

Overall 0.0366% 591/1,614,028 alleles · rare exomes 463/1,461,812 · genomes 128/152,216 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.217%	461
Ashkenazi Jewishnot grpmax-eligible	0.213%	470
Admixed Americangrpmax	0.203%	492
Middle Eastern	0.165%	606
Remaining individualsnot grpmax-eligible	0.072%	1,389
European (non-Finnish)	0.0162%	6,178
African / African-American	0.016%	6,252
South Asian	0.00988%	10,118

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.Ala423=
Coding: c.1269C>T
MANE Select: NM_005554
dbSNP: rs145246640
Type: single nucleotide variant
Location: chr12:52488483 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 423: the if rod domain; the 'coil 2' region

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

Similar variants

KRT6A p.Ala423Val Uncertain significance ★ ⚠ 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-ala423 (accessed [today's date]).

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