Is KRT12 p.Arg187Gly (c.559A>G) pathogenic?

KRT12 p.Arg187Gly (c.559A>G) is classified Uncertain significance in KRT12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.2746); Very rare (popmax 0.0011%, sas); Associated with corneal dystrophy, Meesmann, 1.

What condition is associated with KRT12 p.Arg187Gly (c.559A>G)?

KRT12 p.Arg187Gly (c.559A>G) is associated with corneal dystrophy, Meesmann, 1 (ClinVar).

How common is KRT12 p.Arg187Gly (c.559A>G) in the general population?

KRT12 p.Arg187Gly (c.559A>G) 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.Arg187Gly (c.559A>G)?

AlphaMissense predicts likely benign (score 0.2746) — an in-silico prediction, not a clinical call.

KRT12 p.Arg187Gly

c.559A>G · VCV4292051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

corneal dystrophy, Meesmann, 1

Computational evidence

Protein change
AlphaMissense	0.2746	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -11.76	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 2.3	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	24.4	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 · 1/91,064 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,740 alleles · very rare exomes 3/1,461,478 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,064
European (non-Finnish)	0.00017%	589,835

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.Arg187Gly
Coding: c.559A>G
MANE Select: NM_000223
Type: single nucleotide variant
Location: chr17:40866628 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 187: the if rod domain; the 'coil 1b' 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.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
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-arg187gly (accessed [today's date]).

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