Is KRT6A p.Val398Phe (c.1192G>T) pathogenic?

KRT6A p.Val398Phe (c.1192G>T) is classified Uncertain significance in KRT6A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.8708); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with KRT6A p.Val398Phe (c.1192G>T)?

KRT6A p.Val398Phe (c.1192G>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6A p.Val398Phe (c.1192G>T) in the general population?

KRT6A p.Val398Phe (c.1192G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about KRT6A p.Val398Phe (c.1192G>T)?

AlphaMissense predicts likely pathogenic (score 0.8708) — an in-silico prediction, not a clinical call.

KRT6A p.Val398Phe

c.1192G>T · VCV4095022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8708	likely pathogenic
REVEL	0.63	indeterminate
SaProt	LLR -14.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.93	GERP 1.9
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,892 alleles · very rare

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: KRT6A
Protein: p.Val398Phe
Coding: c.1192G>T
MANE Select: NM_005554
Type: single nucleotide variant
Location: chr12:52489954 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 398: the if rod domain; the 'coil 2' region

Full KRT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT6A p.Val398Ile Uncertain significance ★ ⚠ same residue
KRT6A p.Ala403Thr Uncertain significance ★★ ⚠ same condition
KRT6A p.Arg16Trp Uncertain significance ★★ ⚠ same condition
KRT6A p.Arg240Gly Uncertain significance ★★ same condition
KRT6A p.Gly202Ser Uncertain significance ★★ ⚠ same condition
KRT6A p.Gly510Asp Uncertain significance ★★ same condition
KRT6A p.Lys400Gln Uncertain significance ★★ ⚠ same condition
KRT6A p.Val282Phe Uncertain significance ★★ ⚠ same condition

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/krt6a-p-val398phe (accessed [today's date]).

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