Is KRT5 p.Ala424Pro (c.1270G>C) pathogenic?

KRT5 p.Ala424Pro (c.1270G>C) is classified Likely pathogenic in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-06). AlphaMissense: likely pathogenic (0.9941); Very rare (popmax 0.00167%, amr).

How common is KRT5 p.Ala424Pro (c.1270G>C) in the general population?

KRT5 p.Ala424Pro (c.1270G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KRT5 p.Ala424Pro (c.1270G>C)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

KRT5 p.Ala424Pro

c.1270G>C · rs748836260 · VCV1198522

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic ✓ concordant with ClinVar · top 7% in KRT5
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -11.95	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 7.7	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,753 bp · p 0.69 · regional, not allelic
Overall
CADD	26.8	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 0.00167% Admixed American · 1/60,010 alleles

Overall 6.2e-05% 1/1,614,146 alleles · very rare exomes 1/1,461,890 · genomes 0/152,256 · joint denominator

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: KRT5
Protein: p.Ala424Pro
Coding: c.1270G>C
MANE Select: NM_000424
dbSNP: rs748836260
Type: single nucleotide variant
Location: chr12:52516806 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 424: the if rod domain; an α-helix; a UniProt-annotated variant site (in ddd1); the 'coil 2' region

Full KRT5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT5 c.555+1G>A Pathogenic ★★ same type
KRT5 p.Ala428Thr Pathogenic/Likely pathogenic ★★ same type
KRT5 p.Ala428Val Pathogenic/Likely pathogenic ★★ same type
KRT5 p.Arg165Ser Pathogenic ★★ same type
KRT5 p.Arg331Cys Pathogenic/Likely pathogenic ★★ same type
KRT5 p.Arg331His Pathogenic/Likely pathogenic ★★ same type
KRT5 p.Asn176Ser Pathogenic/Likely pathogenic ★★ same type
KRT5 p.Asn177Ser 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/krt5-p-ala424pro (accessed [today's date]).

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