Is KRT6B p.Pro125Ser (c.373C>T) pathogenic?

KRT6B p.Pro125Ser (c.373C>T) is classified Conflicting classifications of pathogenicity in KRT6B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0406%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRT6B p.Pro125Ser (c.373C>T)?

KRT6B p.Pro125Ser (c.373C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6B p.Pro125Ser (c.373C>T) in the general population?

KRT6B p.Pro125Ser (c.373C>T) is ultra-rare (popmax 0.0406%, nfe) (gnomAD).

What do computational predictors say about KRT6B p.Pro125Ser (c.373C>T)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

KRT6B p.Pro125Ser

c.373C>T · rs202222264 · VCV2266454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -6.26	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 -20	GERP -3.7
Regional constraint	o/e 0.13	constrained · MANE · 210 bp · p 3.9e-17 · regional, not allelic
Overall
CADD	0.826	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 0.0406% European (non-Finnish) · 479/1,179,946 alleles

Filtering AF 0.0376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0364%

Overall 0.031% 500/1,613,144 alleles · ultra-rare exomes 448/1,461,580 · genomes 52/151,564 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0406%	2,463
Finnishnot grpmax-eligible	0.0172%	5,822
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Remaining individualsnot grpmax-eligible	0.00641%	15,612
African / African-American	0.00269%	37,174
Admixed American	0.00167%	60,006

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.Pro125Ser
Coding: c.373C>T
MANE Select: NM_005555
dbSNP: rs202222264
Type: single nucleotide variant
Location: chr12:52451706 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 125: 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-pro125ser (accessed [today's date]).

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