Is KRT12 p.Gly439Asp (c.1316G>A) pathogenic?

KRT12 p.Gly439Asp (c.1316G>A) is classified Uncertain significance in KRT12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-23). AlphaMissense: likely benign (0.092); Very rare (popmax 0.00305%, nfe).

How common is KRT12 p.Gly439Asp (c.1316G>A) in the general population?

KRT12 p.Gly439Asp (c.1316G>A) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about KRT12 p.Gly439Asp (c.1316G>A)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

KRT12 p.Gly439Asp

c.1316G>A · rs1305982561 · VCV2431007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.28	loss · gain 0.03 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00305% European (non-Finnish) · 36/1,179,904 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00235% 38/1,613,910 alleles · very rare exomes 37/1,461,664 · genomes 1/152,246 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,775
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: KRT12
Protein: p.Gly439Asp
Coding: c.1316G>A
MANE Select: NM_000223
dbSNP: rs1305982561
Type: single nucleotide variant
Location: chr17:40863123 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 439: the if rod domain; the 'tail' region

Full KRT12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT12 p.Met129Val Pathogenic/Likely pathogenic ★★ same type
KRT12 p.Asp213Tyr Uncertain significance ★★ ⚠ same type
KRT12 p.Gln486Glu Uncertain significance ★★ ⚠ same type
KRT12 p.Ile195Phe Uncertain significance ★★ ⚠ same type
KRT12 p.Val228Ile Uncertain significance ★★ ⚠ same type
KRT12 c.808-17T>A Benign/Likely benign ★★ same type
KRT12 p.Arg20Trp Benign ★★ ⚠ same type
KRT12 p.Gln475Arg Likely benign ★★ ⚠ same type

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/krt12-p-gly439asp (accessed [today's date]).

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