Is KRT6B p.Arg375Ser (c.1123C>A) pathogenic?

KRT6B p.Arg375Ser (c.1123C>A) is classified Uncertain significance in KRT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-01). AlphaMissense: likely pathogenic (0.9162); Very rare (popmax 0.000678%, nfe).

How common is KRT6B p.Arg375Ser (c.1123C>A) in the general population?

KRT6B p.Arg375Ser (c.1123C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about KRT6B p.Arg375Ser (c.1123C>A)?

AlphaMissense predicts likely pathogenic (score 0.9162) — an in-silico prediction, not a clinical call.

KRT6B p.Arg375Ser

c.1123C>A · VCV3603422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9162	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -13.07	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 -16	GERP -0.24
Regional constraint	o/e 1.05	unconstrained · MANE · 3,349 bp · p 0.25 · regional, not allelic
Overall
CADD	22.7	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 0.000678% European (non-Finnish) · 8/1,179,914 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,584 alleles · very rare exomes 7/1,461,764 · genomes 1/151,820 · 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.Arg375Ser
Coding: c.1123C>A
MANE Select: NM_005555
Type: single nucleotide variant
Location: chr12:52448922 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 375: the if rod domain; the 'coil 2' region

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

Similar variants

KRT6B p.Arg375His Uncertain significance ★★ ⚠ same residue
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.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-arg375ser (accessed [today's date]).

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