Is KRT4 p.Val8Asp (c.23T>A) pathogenic?

KRT4 p.Val8Asp (c.23T>A) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.186); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Val8Asp (c.23T>A)?

KRT4 p.Val8Asp (c.23T>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Val8Asp (c.23T>A) in the general population?

KRT4 p.Val8Asp (c.23T>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about KRT4 p.Val8Asp (c.23T>A)?

AlphaMissense predicts likely benign (score 0.186) — an in-silico prediction, not a clinical call.

KRT4 p.Val8Asp

c.23T>A · VCV4045031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.186	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.9, phastCons 0.94
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	22.4	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 0.000424% European (non-Finnish) · 5/1,179,842 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,762 alleles · very rare exomes 3/1,461,546 · genomes 2/152,216 · joint denominator

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.Val8Asp
Coding: c.23T>A
MANE Select: NM_002272
Type: single nucleotide variant
Location: chr12:52814036 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 8: the 'head' 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-val8asp (accessed [today's date]).

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