Is KRT12 p.Arg20Trp (c.58C>T) pathogenic?

KRT12 p.Arg20Trp (c.58C>T) is classified Benign in KRT12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1207); Common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about KRT12 p.Arg20Trp (c.58C>T)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

KRT12 p.Arg20Trp

Q: How common is KRT12 p.Arg20Trp (c.58C>T) in the general population?

KRT12 p.Arg20Trp (c.58C>T) is common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.58C>T · rs17566772 · VCV1585972

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -12.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -2.4
Regional constraint	o/e 0.94	unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic
Overall
CADD	16.37	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 10.5% Admixed American · 6,283/60,018 alleles

Filtering AF 10.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 7.95% 128,133/1,612,736 alleles · common exomes 118,364/1,460,484 · genomes 9,769/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	10.5%	10
Finnishnot grpmax-eligible	8.83%	11
European (non-Finnish)	8.5%	12
Middle Eastern	8.22%	12
South Asian	7.45%	13
Remaining individualsnot grpmax-eligible	7.3%	14
Ashkenazi Jewishnot grpmax-eligible	6.41%	16
African / African-American	2.23%	45
East Asian	1.33%	75
Amishnot grpmax-eligible	0.548%	182

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.Arg20Trp
Coding: c.58C>T
MANE Select: NM_000223
dbSNP: rs17566772
Type: single nucleotide variant
Location: chr17:40867129 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.57
Residue 20: a UniProt-annotated variant site (in); the 'head' region; the 'disordered' region

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

Similar variants

KRT12 p.Arg20= Likely benign ★ same residue
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.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-arg20trp (accessed [today's date]).

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