Is KRT4 p.Arg366Trp (c.1096C>T) pathogenic?

KRT4 p.Arg366Trp (c.1096C>T) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: likely benign (0.2044); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Arg366Trp (c.1096C>T)?

KRT4 p.Arg366Trp (c.1096C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Arg366Trp (c.1096C>T) in the general population?

KRT4 p.Arg366Trp (c.1096C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about KRT4 p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.2044) — an in-silico prediction, not a clinical call.

KRT4 p.Arg366Trp

c.1096C>T · VCV4045029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2044	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -12.49	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -3.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	25.4	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 0.00549% South Asian · 5/91,074 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00124% 20/1,613,970 alleles · very rare exomes 18/1,461,882 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-American	0.00134%	74,892
European (non-Finnish)	0.00102%	98,334

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.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_002272
Type: single nucleotide variant
Location: chr12:52808323 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 366: the if rod domain; the 'coil 2' 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-arg366trp (accessed [today's date]).

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