Is KRT5 p.Val293Ile (c.877G>A) pathogenic?

KRT5 p.Val293Ile (c.877G>A) is classified Uncertain significance in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.3628); Very rare (popmax 0.0028%, nfe); Associated with epidermolysis bullosa simplex.

What condition is associated with KRT5 p.Val293Ile (c.877G>A)?

KRT5 p.Val293Ile (c.877G>A) is associated with epidermolysis bullosa simplex (ClinVar).

How common is KRT5 p.Val293Ile (c.877G>A) in the general population?

KRT5 p.Val293Ile (c.877G>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about KRT5 p.Val293Ile (c.877G>A)?

AlphaMissense predicts ambiguous (score 0.3628) — an in-silico prediction, not a clinical call.

KRT5 p.Val293Ile

c.877G>A · rs886049625 · VCV309564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

epidermolysis bullosa simplex

Computational evidence

Protein change
AlphaMissense	0.3628	ambiguous
REVEL	0.393	indeterminate
SaProt	LLR -8.40	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 399 bp · p 0.66 · regional, not allelic
Overall
CADD	24.6	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 0.0028% European (non-Finnish) · 33/1,180,036 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00223% 36/1,614,124 alleles · very rare exomes 33/1,461,874 · genomes 3/152,250 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.0028%	35,759
African / African-American	0.00133%	74,946

Remaining individuals 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: KRT5
Protein: p.Val293Ile
Coding: c.877G>A
MANE Select: NM_000424
dbSNP: rs886049625
Type: single nucleotide variant
Location: chr12:52517947 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 293: the if rod domain; a UniProt-annotated variant site (in ddd1); the 'coil 1b' region

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

Disease context

epidermolysis bullosa simplex — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT5 p.Ala428Thr Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Ala428Val Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu170Lys Pathogenic ★★ same condition
KRT5 p.Glu466Gln Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu477Lys Pathogenic ★★ same condition
KRT5 p.Leu196Pro Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Leu463Pro Pathogenic ★★ same condition
KRT5 p.Pro25Leu 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-val293ile (accessed [today's date]).

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