Is KRT12 p.Val228Ile (c.682G>A) pathogenic?

KRT12 p.Val228Ile (c.682G>A) is classified Uncertain significance in KRT12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-13). AlphaMissense: likely benign (0.1576); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with KRT12 p.Val228Ile (c.682G>A)?

KRT12 p.Val228Ile (c.682G>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT12 p.Val228Ile (c.682G>A) in the general population?

KRT12 p.Val228Ile (c.682G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about KRT12 p.Val228Ile (c.682G>A)?

AlphaMissense predicts likely benign (score 0.1576) — an in-silico prediction, not a clinical call.

KRT12 p.Val228Ile

c.682G>A · rs770184655 · VCV3116321

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1576	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -10.87	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 3.3	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	22.9	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 0.00891% East Asian · 4/44,884 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00316% 51/1,614,224 alleles · very rare exomes 43/1,461,874 · genomes 8/152,350 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,221
Admixed American	0.00833%	12,005
Finnishnot grpmax-eligible	0.00781%	12,808
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.00533%	18,767
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.0022%	45,386
South Asian	0.0022%	45,543

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.Val228Ile
Coding: c.682G>A
MANE Select: NM_000223
dbSNP: rs770184655
Type: single nucleotide variant
Location: chr17:40864931 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 228: the if rod domain; the 'coil 1b' region

Full KRT12 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

KRT12 p.Met129Val Pathogenic/Likely pathogenic ★★ same condition
KRT12 p.Asp213Tyr Uncertain significance ★★ ⚠ same condition
KRT12 p.Gln486Glu Uncertain significance ★★ ⚠ same condition
KRT12 p.Ile195Phe Uncertain significance ★★ ⚠ same condition
KRT12 p.Ala149Val Uncertain significance ★ ⚠ same condition
KRT12 p.Ala171Thr Uncertain significance ★ ⚠ same condition
KRT12 p.Ala207Val Uncertain significance ★ ⚠ same condition
KRT12 p.Ala35Pro 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/krt12-p-val228ile (accessed [today's date]).

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