Is KRT1 p.Arg65Trp (c.193C>T) pathogenic?

KRT1 p.Arg65Trp (c.193C>T) is classified Likely benign in KRT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-26). AlphaMissense: ambiguous (0.4966); Rare (popmax 0.275%, afr).

How common is KRT1 p.Arg65Trp (c.193C>T) in the general population?

KRT1 p.Arg65Trp (c.193C>T) is rare (popmax 0.275%, afr) (gnomAD).

What do computational predictors say about KRT1 p.Arg65Trp (c.193C>T)?

AlphaMissense predicts ambiguous (score 0.4966) — an in-silico prediction, not a clinical call.

KRT1 p.Arg65Trp

c.193C>T · rs116444444 · VCV786929

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4966 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.275%, afr)

Computational evidence

Protein change
AlphaMissense	0.4966	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -13.67	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.6, phastCons 0.001
Regional constraint	o/e 0.96	unconstrained · MANE · 5,152 bp · p 0.25 · regional, not allelic
Overall
CADD	23.7	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 0.275% African / African-American · 205/74,592 alleles

Filtering AF 0.244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.0532% 854/1,604,000 alleles · rare exomes 716/1,452,276 · genomes 138/151,724 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.275%	364
European (non-Finnish)	0.0516%	1,939
Remaining individualsnot grpmax-eligible	0.0418%	2,393
Admixed American	0.0208%	4,809
East Asian	0.0113%	8,887

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: KRT1
Protein: p.Arg65Trp
Coding: c.193C>T
MANE Select: NM_006121
dbSNP: rs116444444
Type: single nucleotide variant
Location: chr12:52680156 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 65: the 'head' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT1 p.Arg65Gln Likely benign ★ same residue
KRT1 c.1255-1G>T Pathogenic ★★ same type
KRT1 c.591+1G>C Pathogenic ★★ same type
KRT1 p.Asn188Lys Pathogenic ★★ same type
KRT1 p.Asn188Ser Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile195Asn Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile479Thr Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Leu187Phe Pathogenic ★★ 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/krt1-p-arg65trp (accessed [today's date]).

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