Is KRT6A p.Asp273= (c.819T>C) pathogenic?

KRT6A p.Asp273= (c.819T>C) is classified Benign in KRT6A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 41.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pachyonychia congenita 3.

What condition is associated with KRT6A p.Asp273= (c.819T>C)?

KRT6A p.Asp273= (c.819T>C) is associated with pachyonychia congenita 3 (ClinVar).

How is Pachyonychia congenita inherited?

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

KRT6A p.Asp273=

Q: How common is KRT6A p.Asp273= (c.819T>C) in the general population?

KRT6A p.Asp273= (c.819T>C) is common (popmax 41.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.819T>C · rs12578949 · VCV1300086

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 41.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

pachyonychia congenita 3

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 -13	GERP -3.8
Overall
CADD	0.116	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 41.3% African / African-American · 30,929/74,836 alleles

Filtering AF 40.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.8%

Overall 24% 386,448/1,612,666 alleles · common exomes 341,085/1,460,728 · genomes 45,363/151,938 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	42.9%	2
African / African-Americangrpmax	41.3%	2
Admixed American	40%	3
Finnishnot grpmax-eligible	25.9%	4
Remaining individualsnot grpmax-eligible	24.8%	4
Ashkenazi Jewishnot grpmax-eligible	24.5%	4
Middle Eastern	24.1%	4
South Asian	23.9%	4
European (non-Finnish)	22.1%	5
East Asian	16.8%	6

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: KRT6A
Protein: p.Asp273=
Coding: c.819T>C
MANE Select: NM_005554
dbSNP: rs12578949
Type: single nucleotide variant
Location: chr12:52490951 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 273: the if rod domain; the 'coil 1b' region

Full KRT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pachyonychia congenita 3 — 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

KRT6A c.1460-1G>C Pathogenic/Likely pathogenic ★★ same condition
KRT6A p.Asn171Lys Pathogenic ★★ same condition
KRT6A p.Asn171Ser Pathogenic ★★ same condition
KRT6A p.Glu163Lys Pathogenic ★★ same condition
KRT6A p.Glu472Lys Pathogenic/Likely pathogenic ★★ same condition
KRT6A p.Leu170Phe Pathogenic ★★ same condition
KRT6A p.Arg375His Uncertain significance ★★ ⚠ same condition
KRT6A p.Lys550Asn 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/krt6a-p-asp273 (accessed [today's date]).

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