Is KRT6B p.Arg386Pro (c.1157G>C) pathogenic?

KRT6B p.Arg386Pro (c.1157G>C) is classified Uncertain significance in KRT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with KRT6B p.Arg386Pro (c.1157G>C)?

KRT6B p.Arg386Pro (c.1157G>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6B p.Arg386Pro (c.1157G>C) in the general population?

KRT6B p.Arg386Pro (c.1157G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KRT6B p.Arg386Pro (c.1157G>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

KRT6B p.Arg386Pro

c.1157G>C · VCV3536119

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic · top 2% in KRT6B
REVEL	0.678	pathogenic-leaning
SaProt	LLR -16.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -1.2
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 0.00167% Admixed American · 1/59,990 alleles

Overall 0.000124% 2/1,614,012 alleles · very rare exomes 2/1,461,878 · genomes 0/152,134 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
European (non-Finnish)	8.47e-05%	1,179,997

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.Arg386Pro
Coding: c.1157G>C
MANE Select: NM_005555
Type: single nucleotide variant
Location: chr12:52448888 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 386: the if rod domain; the 'coil 2' 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.Arg386His Uncertain significance ★★ same residue
KRT6B p.Ala403Val Uncertain significance ★★ ⚠ same condition
KRT6B p.Arg260His Uncertain significance ★★ same condition
KRT6B p.Arg375His 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-arg386pro (accessed [today's date]).

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