Is KRT1 p.Ser338Pro (c.1012T>C) pathogenic?

KRT1 p.Ser338Pro (c.1012T>C) is classified Uncertain significance in KRT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.9879); Absent from gnomAD v4.1.

How common is KRT1 p.Ser338Pro (c.1012T>C) in the general population?

KRT1 p.Ser338Pro (c.1012T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRT1 p.Ser338Pro (c.1012T>C)?

AlphaMissense predicts likely pathogenic (score 0.9879) — an in-silico prediction, not a clinical call.

KRT1 p.Ser338Pro

c.1012T>C · rs2121004096 · VCV1352039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9879 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9879	likely pathogenic · top 5% in KRT1
REVEL	0.666	pathogenic-leaning
SaProt	LLR -12.07	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 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,152 bp · p 0.25 · regional, not allelic
Overall
CADD	27.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KRT1
Protein: p.Ser338Pro
Coding: c.1012T>C
MANE Select: NM_006121
dbSNP: rs2121004096
Type: single nucleotide variant
Location: chr12:52677432 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 338: the if rod domain; the 'linker 12' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT1 c.1255-1G>T Pathogenic ★★ same type
KRT1 c.591+1G>C Pathogenic ★★ same type
KRT1 p.Asn188Lys Pathogenic ★★ same type
KRT1 p.Asn188Ser Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile195Asn Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile479Thr Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Leu187Phe Pathogenic ★★ same type
KRT1 p.Leu485Phe 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/krt1-p-ser338pro (accessed [today's date]).

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