Is KRT6C p.Thr139= (c.417C>T) pathogenic?

KRT6C p.Thr139= (c.417C>T) is classified Benign in KRT6C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 64.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with palmoplantar keratoderma, nonepidermolytic, focal or diffuse.

What condition is associated with KRT6C p.Thr139= (c.417C>T)?

KRT6C p.Thr139= (c.417C>T) is associated with palmoplantar keratoderma, nonepidermolytic, focal or diffuse (ClinVar).

KRT6C p.Thr139=

Q: How common is KRT6C p.Thr139= (c.417C>T) in the general population?

KRT6C p.Thr139= (c.417C>T) is common (popmax 64.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering inherited?

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

c.417C>T · rs1053684 · VCV1300099

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 64.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

palmoplantar keratoderma, nonepidermolytic, focal or diffuse

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 -3.6
Overall
CADD	3.087	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 64.1% East Asian · 20,418/31,832 alleles

Filtering AF 63.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.1%

Overall 28.8% 318,749/1,105,858 alleles · common exomes 282,988/1,012,016 · genomes 35,761/93,842 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	64.1%	2
Admixed American	52.2%	2
Amishnot grpmax-eligible	47.5%	2
Ashkenazi Jewishnot grpmax-eligible	41.6%	2
Finnishnot grpmax-eligible	40.6%	2
Remaining individualsnot grpmax-eligible	33.5%	3
Middle Eastern	32.9%	3
South Asian	30.6%	3
African / African-American	27.9%	4
European (non-Finnish)	24.8%	4

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: KRT6C
Protein: p.Thr139=
Coding: c.417C>T
MANE Select: NM_173086
dbSNP: rs1053684
Type: single nucleotide variant
Location: chr12:52473321 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.63
Residue 139: the 'head' region

Full KRT6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

palmoplantar keratoderma, nonepidermolytic, focal or diffuse — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

KRT6C p.Glu472Lys Pathogenic/Likely pathogenic ★★ same condition
KRT6C c.1460-10C>A Benign ★★ same condition
KRT6C c.755+13T>C Benign ★★ same condition
KRT6C c.816+13A>G Benign ★★ same condition
KRT6C p.Ala419= Benign/Likely benign ★★ same condition
KRT6C p.Arg182Gln Benign ★★ same condition
KRT6C p.Gly66= Benign ★★ same condition
KRT6C p.Leu61= 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/krt6c-p-thr139 (accessed [today's date]).

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