Is KRT2 p.Val469Met (c.1405G>A) pathogenic?

KRT2 p.Val469Met (c.1405G>A) is classified Uncertain significance in KRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.325); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with KRT2 p.Val469Met (c.1405G>A)?

KRT2 p.Val469Met (c.1405G>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT2 p.Val469Met (c.1405G>A) in the general population?

KRT2 p.Val469Met (c.1405G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about KRT2 p.Val469Met (c.1405G>A)?

AlphaMissense predicts likely benign (score 0.325) — an in-silico prediction, not a clinical call.

KRT2 p.Val469Met

c.1405G>A · VCV4044849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.325	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -12.33	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 -4.3	GERP -3.7
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	12.9	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 0.00223% East Asian · 1/44,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,614,044 alleles · very rare exomes 5/1,461,890 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000339%	295,010

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: KRT2
Protein: p.Val469Met
Coding: c.1405G>A
MANE Select: NM_000423
Type: single nucleotide variant
Location: chr12:52646804 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 469: the if rod domain; the 'coil 2' region

Full KRT2 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

KRT2 p.Val469Leu Uncertain significance ★ same residue
KRT2 p.Arg544Gln Uncertain significance ★★ ⚠ same condition
KRT2 p.Asn498Ile Uncertain significance ★★ ⚠ same condition
KRT2 p.Val402Met Likely benign ★★ same condition
KRT2 p.Ala190Ser Uncertain significance ★ ⚠ same condition
KRT2 p.Ala278Thr Uncertain significance ★ ⚠ same condition
KRT2 p.Ala350Thr Uncertain significance ★ ⚠ same condition
KRT2 p.Ala369Ser 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/krt2-p-val469met (accessed [today's date]).

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