Is KRT8 p.Ala86Val (c.257C>T) pathogenic?

KRT8 p.Ala86Val (c.257C>T) is classified Uncertain significance in KRT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.138); Very rare (popmax 8.47e-05%, nfe).

How common is KRT8 p.Ala86Val (c.257C>T) in the general population?

KRT8 p.Ala86Val (c.257C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KRT8 p.Ala86Val (c.257C>T)?

AlphaMissense predicts likely benign (score 0.138) — an in-silico prediction, not a clinical call.

KRT8 p.Ala86Val

c.257C>T · VCV4045210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.138 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.138	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 2,719 bp · p 1.1e-06 · regional, not allelic
Overall
CADD	21.0	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 8.47e-05% European (non-Finnish) · 1/1,179,944 alleles

Overall 6.2e-05% 1/1,612,688 alleles · very rare exomes 0/1,460,474 · genomes 1/152,214 · 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: KRT8
Protein: p.Ala86Val
Coding: c.257C>T
MANE Select: NM_002273
Type: single nucleotide variant
Location: chr12:52904725 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 3 PDB
Residue 86: the 'head' region

Full KRT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT8 p.Lys464Asn Uncertain significance ★★ ⚠ same type
KRT8 c.-4T>C Benign ★★ same type
KRT8 p.Ala333= Benign ★★ same type
KRT8 p.Arg341His Benign ★★ same type
KRT8 p.Gly434Ser Benign ★★ same type
KRT8 p.Gly62Cys Benign/Likely benign ★★ ⚠ same type
KRT8 p.Ile63Val Benign/Likely benign ★★ ⚠ same type
KRT8 p.Tyr54His Benign/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/krt8-p-ala86val (accessed [today's date]).

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