Is KRT4 p.Phe498Ser (c.1493T>C) pathogenic?

KRT4 p.Phe498Ser (c.1493T>C) is classified Conflicting classifications of pathogenicity in KRT4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-05). AlphaMissense: likely benign (0.1382); Rare (popmax 0.28%, mid); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Phe498Ser (c.1493T>C)?

KRT4 p.Phe498Ser (c.1493T>C) is associated with Inborn genetic diseases, white sponge nevus 1 (ClinVar).

How common is KRT4 p.Phe498Ser (c.1493T>C) in the general population?

KRT4 p.Phe498Ser (c.1493T>C) is rare (popmax 0.28%, mid) (gnomAD).

What do computational predictors say about KRT4 p.Phe498Ser (c.1493T>C)?

AlphaMissense predicts likely benign (score 0.1382) — an in-silico prediction, not a clinical call.

KRT4 p.Phe498Ser

c.1493T>C · rs377399080 · VCV309668

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1382 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1382	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -3.37	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 5	GERP -2.3, phastCons 0.87
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	16.22	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 0.28% Middle Eastern · 17/6,062 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0192% 310/1,614,162 alleles · rare exomes 266/1,461,892 · genomes 44/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	357
Ashkenazi Jewishnot grpmax-eligible	0.152%	658
South Asian	0.0604%	1,656
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.03%	3,334
European (non-Finnish)	0.0129%	7,763
African / African-American	0.00133%	75,024

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.Phe498Ser
Coding: c.1493T>C
MANE Select: NM_002272
dbSNP: rs377399080
Type: single nucleotide variant
Location: chr12:52807139 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 498: the 'tail' 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

Also linked: white sponge nevus 1

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-phe498ser (accessed [today's date]).

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