Is KRT4 p.Val65Met (c.193G>A) pathogenic?

KRT4 p.Val65Met (c.193G>A) is classified Conflicting classifications of pathogenicity in KRT4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-04-07). AlphaMissense: likely benign (0.1213); Ultra-rare (popmax 0.0493%, mid); Associated with white sponge nevus 1.

What condition is associated with KRT4 p.Val65Met (c.193G>A)?

KRT4 p.Val65Met (c.193G>A) is associated with white sponge nevus 1 (ClinVar).

How common is KRT4 p.Val65Met (c.193G>A) in the general population?

KRT4 p.Val65Met (c.193G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

How is White sponge nevus inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KRT4 p.Val65Met (c.193G>A)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

KRT4 p.Val65Met

c.193G>A · rs754420448 · VCV881697

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

white sponge nevus 1

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2.2
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	6.194	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00291% 47/1,614,028 alleles · ultra-rare exomes 44/1,461,750 · genomes 3/152,278 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.004%	24,985
European (non-Finnish)	0.00314%	31,891
South Asian	0.0011%	91,086

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: KRT4
Protein: p.Val65Met
Coding: c.193G>A
MANE Select: NM_002272
dbSNP: rs754420448
Type: single nucleotide variant
Location: chr12:52813866 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 65: the 'head' region

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

Disease context

white sponge nevus 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For White sponge nevus (Orphanet):

Inheritance: Autosomal dominant

Similar variants

KRT4 p.Ala106Gly Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp153Asn Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp247Glu Uncertain significance ★★ same condition
KRT4 c.1346+15A>G Benign ★★ same condition
KRT4 c.1346+15A>T Likely benign ★★ same condition
KRT4 c.1381+15C>T Benign ★★ same condition
KRT4 c.678-14G>A Benign ★★ same condition
KRT4 c.678-3C>T Benign ★★ 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-val65met (accessed [today's date]).

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