Is KRT83 p.Ala460Pro (c.1378G>C) pathogenic?

KRT83 p.Ala460Pro (c.1378G>C) is classified Uncertain significance in KRT83 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: likely benign (0.1109); Ultra-rare (popmax 0.0226%, eas).

How common is KRT83 p.Ala460Pro (c.1378G>C) in the general population?

KRT83 p.Ala460Pro (c.1378G>C) is ultra-rare (popmax 0.0226%, eas) (gnomAD).

What do computational predictors say about KRT83 p.Ala460Pro (c.1378G>C)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

KRT83 p.Ala460Pro

c.1378G>C · rs1427065959 · VCV2598011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.82, phastCons 0.7
Regional constraint	o/e 0.98	unconstrained · MANE · 6,701 bp · p 0.63 · regional, not allelic
Overall
CADD	19.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0226% East Asian · 10/44,232 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00928%

Overall 0.000941% 15/1,594,574 alleles · ultra-rare exomes 10/1,442,350 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0226%	4,423
Remaining individualsnot grpmax-eligible	0.00649%	15,417
European (non-Finnish)	8.54e-05%	1,171,160

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: KRT83
Protein: p.Ala460Pro
Coding: c.1378G>C
MANE Select: NM_002282
dbSNP: rs1427065959
Type: single nucleotide variant
Location: chr12:52314735 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 460: the 'tail' region

Full KRT83 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT83 p.Ala460= Likely benign same residue
KRT83 p.Glu407Lys Likely pathogenic ★★ same type
KRT83 p.Arg130Cys Uncertain significance ★★ ⚠ same type
KRT83 p.Arg168Trp Uncertain significance ★★ ⚠ same type
KRT83 p.Arg272Gln Uncertain significance ★★ ⚠ same type
KRT83 p.Arg272Trp Uncertain significance ★★ ⚠ same type
KRT83 p.Arg293His Uncertain significance ★★ ⚠ same type
KRT83 p.Arg321Cys Uncertain significance ★★ ⚠ 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/krt83-p-ala460pro (accessed [today's date]).

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