Is KRT6B p.Arg415Ser (c.1243C>A) pathogenic?

KRT6B p.Arg415Ser (c.1243C>A) is classified Uncertain significance in KRT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). AlphaMissense: likely pathogenic (0.8771); Very rare (popmax 0.00102%, nfe); Associated with pachyonychia congenita 4.

What condition is associated with KRT6B p.Arg415Ser (c.1243C>A)?

KRT6B p.Arg415Ser (c.1243C>A) is associated with pachyonychia congenita 4 (ClinVar).

How common is KRT6B p.Arg415Ser (c.1243C>A) in the general population?

KRT6B p.Arg415Ser (c.1243C>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Pachyonychia congenita inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KRT6B p.Arg415Ser (c.1243C>A)?

AlphaMissense predicts likely pathogenic (score 0.8771) — an in-silico prediction, not a clinical call.

KRT6B p.Arg415Ser

c.1243C>A · VCV3891534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pachyonychia congenita 4

Computational evidence

Protein change
AlphaMissense	0.8771	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -12.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.47	GERP 0.83
Regional constraint	o/e 1.05	unconstrained · MANE · 3,349 bp · p 0.25 · regional, not allelic
Overall
CADD	24.6	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 0.00102% European (non-Finnish) · 12/1,180,024 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,126 alleles · very rare exomes 12/1,461,876 · genomes 0/152,250 · 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.Arg415Ser
Coding: c.1243C>A
MANE Select: NM_005555
Type: single nucleotide variant
Location: chr12:52447959 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 415: the if rod domain; the 'coil 2' region

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

Disease context

pachyonychia congenita 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pachyonychia congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

KRT6B p.Arg415His Likely benign ★★ ⚠ same residue
KRT6B p.Arg415Cys Uncertain significance ★ ⚠ same residue
KRT6B p.Glu461Lys Pathogenic/Likely pathogenic ★★ same condition
KRT6B p.Glu472Lys Pathogenic ★★ same condition
KRT6B p.Arg375His Uncertain significance ★★ ⚠ same condition
KRT6B p.Ala407= Benign ★★ same condition
KRT6B p.Asn21Ser Benign ★★ same condition
KRT6B p.Asp396Asn Benign/Likely benign ★★ ⚠ 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-arg415ser (accessed [today's date]).

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