Is KRT12 p.Arg421Gly (c.1261C>G) pathogenic?

KRT12 p.Arg421Gly (c.1261C>G) is classified Uncertain significance in KRT12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-02). AlphaMissense: likely benign (0.1443); Very rare (popmax 8.47e-05%, nfe).

How common is KRT12 p.Arg421Gly (c.1261C>G) in the general population?

KRT12 p.Arg421Gly (c.1261C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KRT12 p.Arg421Gly (c.1261C>G)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

KRT12 p.Arg421Gly

c.1261C>G · VCV3661214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign
REVEL	0.707	pathogenic-leaning
SaProt	LLR -9.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.02, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	24.3	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.2e-05% 1/1,614,144 alleles · very rare exomes 1/1,461,786 · genomes 0/152,358 · 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.Arg421Gly
Coding: c.1261C>G
MANE Select: NM_000223
Type: single nucleotide variant
Location: chr17:40863178 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 421: the if rod domain; the 'coil 2' region

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

Similar variants

KRT12 p.Met129Val Pathogenic/Likely pathogenic ★★ same type
KRT12 p.Asp213Tyr Uncertain significance ★★ ⚠ same type
KRT12 p.Gln486Glu Uncertain significance ★★ ⚠ same type
KRT12 p.Ile195Phe Uncertain significance ★★ ⚠ same type
KRT12 p.Val228Ile Uncertain significance ★★ ⚠ same type
KRT12 c.808-17T>A Benign/Likely benign ★★ same type
KRT12 p.Arg20Trp Benign ★★ ⚠ same type
KRT12 p.Gln475Arg Likely benign ★★ ⚠ same type

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-arg421gly (accessed [today's date]).

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