Is KRT6B p.Phe127Val (c.379T>G) pathogenic?

KRT6B p.Phe127Val (c.379T>G) is classified Uncertain significance in KRT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-04). AlphaMissense: ambiguous (0.5346); Very rare (popmax 0.000248%).

How common is KRT6B p.Phe127Val (c.379T>G) in the general population?

KRT6B p.Phe127Val (c.379T>G) is very rare (popmax 0.000248%) (gnomAD).

What do computational predictors say about KRT6B p.Phe127Val (c.379T>G)?

AlphaMissense predicts ambiguous (score 0.5346) — an in-silico prediction, not a clinical call.

KRT6B p.Phe127Val

c.379T>G · VCV4916953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000248%)

Computational evidence

Protein change
AlphaMissense	0.5346	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -4.73	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.67	GERP 1.7
Regional constraint	o/e 0.13	constrained · MANE · 210 bp · p 3.9e-17 · regional, not allelic
Overall
CADD	22.3	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 0.000248%

Overall 0.000248% 4/1,613,308 alleles · very rare exomes 2/1,461,644 · genomes 2/151,664 · 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: KRT6B
Protein: p.Phe127Val
Coding: c.379T>G
MANE Select: NM_005555
Type: single nucleotide variant
Location: chr12:52451700 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 127: the 'head' region

Full KRT6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT6B p.Glu461Lys Pathogenic/Likely pathogenic ★★ same type
KRT6B p.Glu472Lys Pathogenic ★★ same type
KRT6B p.Ala403Val Uncertain significance ★★ ⚠ same type
KRT6B p.Arg260His Uncertain significance ★★ same type
KRT6B p.Arg375His Uncertain significance ★★ ⚠ same type
KRT6B p.Arg386His Uncertain significance ★★ same type
KRT6B p.Gln208His Uncertain significance ★★ ⚠ same type
KRT6B p.Gln379Arg 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/krt6b-p-phe127val (accessed [today's date]).

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