Is KRT12 p.Leu394Pro (c.1181T>C) pathogenic?

KRT12 p.Leu394Pro (c.1181T>C) is classified Conflicting classifications of pathogenicity in KRT12 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.912); Ultra-rare (popmax 0.0164%, mid); Associated with corneal dystrophy, Meesmann, 1.

What condition is associated with KRT12 p.Leu394Pro (c.1181T>C)?

KRT12 p.Leu394Pro (c.1181T>C) is associated with corneal dystrophy, Meesmann, 1 (ClinVar).

How common is KRT12 p.Leu394Pro (c.1181T>C) in the general population?

KRT12 p.Leu394Pro (c.1181T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Meesmann corneal dystrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KRT12 p.Leu394Pro (c.1181T>C)?

AlphaMissense predicts likely pathogenic (score 0.912) — an in-silico prediction, not a clinical call.

KRT12 p.Leu394Pro

c.1181T>C · rs370179526 · VCV2628021

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

corneal dystrophy, Meesmann, 1

Computational evidence

Protein change
AlphaMissense	0.912	likely pathogenic · top 3% in KRT12
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -14.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	26.3	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00266% 43/1,613,878 alleles · ultra-rare exomes 38/1,461,640 · genomes 5/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00339%	29,500
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,950

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.Leu394Pro
Coding: c.1181T>C
MANE Select: NM_000223
dbSNP: rs370179526
Type: single nucleotide variant
Location: chr17:40863258 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 394: the if rod domain; the 'coil 2' region

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

Disease context

corneal dystrophy, Meesmann, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Meesmann corneal dystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

KRT12 p.Pro15Ser Benign ★★ same condition
KRT12 p.Met129Thr Pathogenic ★ same condition
KRT12 p.Arg187Gly Uncertain significance ★ ⚠ same condition
KRT12 p.Asp175Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
KRT12 p.Glu330Ter Uncertain significance ★ same condition
KRT12 p.Leu384Pro Uncertain significance ★ ⚠ same condition
KRT12 p.Arg135Gly Pathogenic same condition
KRT12 p.Arg135Ile Pathogenic 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-leu394pro (accessed [today's date]).

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