Is KRT12 p.Val143Leu (c.427G>C) pathogenic?

KRT12 p.Val143Leu (c.427G>C) is classified Pathogenic in KRT12 (ClinVar, No assertion criteria, 2 submitters; last evaluated 1997-06-01). AlphaMissense: likely pathogenic (0.935); Very rare (popmax 0.0011%, sas); Associated with corneal dystrophy, Meesmann, 1.

What condition is associated with KRT12 p.Val143Leu (c.427G>C)?

KRT12 p.Val143Leu (c.427G>C) is associated with corneal dystrophy, Meesmann, 1 (ClinVar).

How common is KRT12 p.Val143Leu (c.427G>C) in the general population?

KRT12 p.Val143Leu (c.427G>C) is very rare (popmax 0.0011%, sas) (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.Val143Leu (c.427G>C)?

AlphaMissense predicts likely pathogenic (score 0.935) — an in-silico prediction, not a clinical call.

KRT12 p.Val143Leu

c.427G>C · rs58343600 · VCV7922

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

corneal dystrophy, Meesmann, 1

Computational evidence

Protein change
AlphaMissense	0.935	likely pathogenic ✓ concordant with ClinVar · top 2% in KRT12
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -13.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	25.6	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 0.0011% South Asian · 1/91,070 alleles

Overall 6.2e-05% 1/1,614,170 alleles · very rare exomes 1/1,461,888 · genomes 0/152,282 · 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: KRT12
Protein: p.Val143Leu
Coding: c.427G>C
MANE Select: NM_000223
dbSNP: rs58343600
Type: single nucleotide variant
Location: chr17:40866760 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 143: the if rod domain; a UniProt-annotated variant site (in mecd1); the 'coil 1a' 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.Leu394Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
KRT12 p.Arg135Gly 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-val143leu (accessed [today's date]).

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