Is KRT6B p.Ala407= (c.1221C>T) pathogenic?

KRT6B p.Ala407= (c.1221C>T) is classified Benign in KRT6B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 71.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with pachyonychia congenita 4.

What condition is associated with KRT6B p.Ala407= (c.1221C>T)?

KRT6B p.Ala407= (c.1221C>T) is associated with pachyonychia congenita 4 (ClinVar).

How is Pachyonychia congenita inherited?

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

KRT6B p.Ala407=

Q: How common is KRT6B p.Ala407= (c.1221C>T) in the general population?

KRT6B p.Ala407= (c.1221C>T) is common (popmax 71.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1221C>T · rs388626 · VCV1269785

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 71.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

pachyonychia congenita 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.8
Overall
CADD	2.775	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 71.9% East Asian · 32,224/44,842 alleles

Filtering AF 71.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 70.9%

Overall 48.8% 787,984/1,613,834 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	71.9%	1
Admixed American	61.9%	2
European (non-Finnish)	48.6%	2
Finnishnot grpmax-eligible	48%	2
Remaining individualsnot grpmax-eligible	47.7%	2
African / African-American	45.1%	2
Middle Eastern	44.9%	2
Ashkenazi Jewishnot grpmax-eligible	44.8%	2
South Asian	38.5%	3
Amishnot grpmax-eligible	30.5%	3

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.Ala407=
Coding: c.1221C>T
MANE Select: NM_005555
dbSNP: rs388626
Type: single nucleotide variant
Location: chr12:52447981 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76
Residue 407: 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.Ala407Thr 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.Asn21Ser Benign ★★ same condition
KRT6B p.Asp396Asn Benign/Likely benign ★★ ⚠ same condition
KRT6B p.Gly499Ser Benign ★★ same condition
KRT6B p.Ile365Val 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-ala407 (accessed [today's date]).

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