Is KRT4 p.Ser219Arg (c.657C>A) pathogenic?

KRT4 p.Ser219Arg (c.657C>A) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.5106); Ultra-rare (popmax 0.0178%, mid); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Ser219Arg (c.657C>A)?

KRT4 p.Ser219Arg (c.657C>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Ser219Arg (c.657C>A) in the general population?

KRT4 p.Ser219Arg (c.657C>A) is ultra-rare (popmax 0.0178%, mid) (gnomAD).

What do computational predictors say about KRT4 p.Ser219Arg (c.657C>A)?

AlphaMissense predicts ambiguous (score 0.5106) — an in-silico prediction, not a clinical call.

KRT4 p.Ser219Arg

c.657C>A · VCV4045025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5106	ambiguous
REVEL	0.437	indeterminate
SaProt	LLR -8.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	0.02	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 0.0178% Middle Eastern · 1/5,622 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,613,372 alleles · ultra-rare exomes 22/1,461,140 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0178%	5,622
European (non-Finnish)	0.0017%	58,991
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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.Ser219Arg
Coding: c.657C>A
MANE Select: NM_002272
Type: single nucleotide variant
Location: chr12:52811783 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 219: the if rod domain; the 'coil 1b' 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.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
KRT4 p.Ala278Glu Uncertain significance ★ ⚠ same condition
KRT4 p.Ala278Val 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-ser219arg (accessed [today's date]).

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