Is KRT12 p.Asp175Asn (c.523G>A) pathogenic?

KRT12 p.Asp175Asn (c.523G>A) is classified Conflicting classifications of pathogenicity in KRT12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.1077); Ultra-rare (popmax 0.0165%, mid); Associated with corneal dystrophy, Meesmann, 1.

What condition is associated with KRT12 p.Asp175Asn (c.523G>A)?

KRT12 p.Asp175Asn (c.523G>A) is associated with corneal dystrophy, Meesmann, 1 (ClinVar).

How common is KRT12 p.Asp175Asn (c.523G>A) in the general population?

KRT12 p.Asp175Asn (c.523G>A) is ultra-rare (popmax 0.0165%, 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.Asp175Asn (c.523G>A)?

AlphaMissense predicts likely benign (score 0.1077) — an in-silico prediction, not a clinical call.

KRT12 p.Asp175Asn

c.523G>A · rs200941376 · VCV2672273

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

corneal dystrophy, Meesmann, 1

Computational evidence

Protein change
AlphaMissense	0.1077	likely benign
REVEL	0.536	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	24.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00112% 18/1,614,166 alleles · ultra-rare exomes 15/1,461,874 · genomes 3/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0134%	7,481
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)	0.000424%	236,005

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.Asp175Asn
Coding: c.523G>A
MANE Select: NM_000223
dbSNP: rs200941376
Type: single nucleotide variant
Location: chr17:40866664 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 175: the if rod domain; the 'linker 1' 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.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-asp175asn (accessed [today's date]).

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