Is KRT4 p.Ser291Phe (c.872C>T) pathogenic?

KRT4 p.Ser291Phe (c.872C>T) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.5772); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Ser291Phe (c.872C>T)?

KRT4 p.Ser291Phe (c.872C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Ser291Phe (c.872C>T) in the general population?

KRT4 p.Ser291Phe (c.872C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRT4 p.Ser291Phe (c.872C>T)?

AlphaMissense predicts likely pathogenic (score 0.5772) — an in-silico prediction, not a clinical call.

KRT4 p.Ser291Phe

c.872C>T · VCV3865559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5772 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5772	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -12.54	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 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	25.8	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: KRT4
Protein: p.Ser291Phe
Coding: c.872C>T
MANE Select: NM_002272
Type: single nucleotide variant
Location: chr12:52808813 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 291: the if rod domain; the 'linker 12' region

Full KRT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT4 p.Ser291Thr Uncertain significance ★ ⚠ same residue
KRT4 p.Ser291= Benign/Likely benign ★★ same residue
KRT4 p.Ala106Gly Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp153Asn Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp247Glu Uncertain significance ★★ same condition
KRT4 p.His398Tyr Likely benign ★★ same condition
KRT4 p.Ala106Thr Uncertain significance ★ ⚠ same condition
KRT4 p.Ala20Asp Uncertain significance ★ ⚠ same condition

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/krt4-p-ser291phe (accessed [today's date]).

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