Is KRT6B p.Leu148Phe (c.442C>T) pathogenic?

KRT6B p.Leu148Phe (c.442C>T) is classified Uncertain significance in KRT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.8554); Very rare (popmax 0.00542%, afr); Associated with Inborn genetic diseases.

What condition is associated with KRT6B p.Leu148Phe (c.442C>T)?

KRT6B p.Leu148Phe (c.442C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6B p.Leu148Phe (c.442C>T) in the general population?

KRT6B p.Leu148Phe (c.442C>T) is very rare (popmax 0.00542%, afr) (gnomAD).

What do computational predictors say about KRT6B p.Leu148Phe (c.442C>T)?

AlphaMissense predicts likely pathogenic (score 0.8554) — an in-silico prediction, not a clinical call.

KRT6B p.Leu148Phe

c.442C>T · rs779355995 · VCV3116577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8554	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -12.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.78, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 1,109 bp · p 6.7e-08 · regional, not allelic
Overall
CADD	22.9	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 0.00542% African / African-American · 4/73,862 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00186% 30/1,612,934 alleles · very rare exomes 28/1,461,724 · genomes 2/151,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00542%	18,466
European (non-Finnish)	0.00212%	47,201
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Leu148Phe
Coding: c.442C>T
MANE Select: NM_005555
dbSNP: rs779355995
Type: single nucleotide variant
Location: chr12:52451637 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 148: the 'head' region

Full KRT6B 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

KRT6B p.Ala403Val Uncertain significance ★★ ⚠ same condition
KRT6B p.Arg260His Uncertain significance ★★ same condition
KRT6B p.Arg375His Uncertain significance ★★ ⚠ same condition
KRT6B p.Arg386His Uncertain significance ★★ same condition
KRT6B p.Gln208His Uncertain significance ★★ ⚠ same condition
KRT6B p.Gln379Arg Uncertain significance ★★ ⚠ same condition
KRT6B p.Gly103Ser Uncertain significance ★★ ⚠ same condition
KRT6B p.Lys281Gln 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/krt6b-p-leu148phe (accessed [today's date]).

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