Is KRT5 p.Ser181Pro (c.541T>C) pathogenic?

KRT5 p.Ser181Pro (c.541T>C) is classified Pathogenic in KRT5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.9974); Absent from gnomAD v4.1; Associated with KRT5-related disorder.

What condition is associated with KRT5 p.Ser181Pro (c.541T>C)?

KRT5 p.Ser181Pro (c.541T>C) is associated with KRT5-related disorder, epidermolysis bullosa simplex 1A, generalized severe (ClinVar).

How common is KRT5 p.Ser181Pro (c.541T>C) in the general population?

KRT5 p.Ser181Pro (c.541T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRT5 p.Ser181Pro (c.541T>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

KRT5 p.Ser181Pro

c.541T>C · rs60715293 · VCV14650

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KRT5-related disorder

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic ✓ concordant with ClinVar · top 4% in KRT5
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -15.44	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 7	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,321 bp · p 0.7 · regional, not allelic
Overall
CADD	32.0	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

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: KRT5
Protein: p.Ser181Pro
Coding: c.541T>C
MANE Select: NM_000424
dbSNP: rs60715293
Type: single nucleotide variant
Location: chr12:52519756 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 181: the if rod domain; a UniProt-annotated variant site (in ddd1); the 'coil 1a' region; a UniProt-annotated variant site (in ebs2a; with laryngeal involvement)

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

Disease context

KRT5-related disorder

Also linked: epidermolysis bullosa simplex 1A, generalized severe

Similar variants

KRT5 p.Ser181del Conflicting classifications of pathogenicity ★ same residue
KRT5 c.555+1G>A Pathogenic ★★ same condition
KRT5 p.Ala428Thr Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Arg331His Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Asn177Ser Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu477Lys Pathogenic ★★ same condition
KRT5 p.Gly476Asp Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Met327Thr Pathogenic ★★ 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/krt5-p-ser181pro (accessed [today's date]).

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