Is KRT1 p.Ile25= (c.75C>T) pathogenic?

KRT1 p.Ile25= (c.75C>T) is classified Benign in KRT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 6.63%, sas) — too common for a highly-penetrant pathogenic allele; Associated with diffuse nonepidermolytic palmoplantar keratoderma.

KRT1 p.Ile25=

Q: What condition is associated with KRT1 p.Ile25= (c.75C>T)?

KRT1 p.Ile25= (c.75C>T) is associated with diffuse nonepidermolytic palmoplantar keratoderma, epidermolytic ichthyosis (ClinVar).

Q: How common is KRT1 p.Ile25= (c.75C>T) in the general population?

KRT1 p.Ile25= (c.75C>T) is common (popmax 6.63%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is KRT1-related diffuse nonepidermolytic keratoderma inherited?

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

c.75C>T · rs828367 · VCV66664

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 6.63%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

diffuse nonepidermolytic palmoplantar keratoderma

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 2.1	GERP 1.6, phastCons 0.98
Overall
CADD	9.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.63% South Asian · 6,041/91,058 alleles

Filtering AF 6.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.44%

Overall 3.79% 61,092/1,613,786 alleles · common exomes 56,514/1,461,888 · genomes 4,578/151,898 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	6.63%	15
Middle Eastern	5.6%	18
Finnishnot grpmax-eligible	4.12%	24
European (non-Finnish)	3.94%	25
Remaining individualsnot grpmax-eligible	3.58%	28
Ashkenazi Jewishnot grpmax-eligible	2.84%	35
Admixed American	1.97%	51
African / African-American	1.21%	83
East Asian	0.823%	122
Amishnot grpmax-eligible	0.11%	912

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: KRT1
Protein: p.Ile25=
Coding: c.75C>T
MANE Select: NM_006121
dbSNP: rs828367
Type: single nucleotide variant
Location: chr12:52680274 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 25: the 'head' region; the 'disordered' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: epidermolytic ichthyosis

For KRT1-related diffuse nonepidermolytic keratoderma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

KRT1 c.1255-1G>T Pathogenic ★★ same condition
KRT1 p.Asn188Lys Pathogenic ★★ same condition
KRT1 p.Leu485Phe Pathogenic/Likely pathogenic ★★ same condition
KRT1 p.Arg86His Uncertain significance ★★ ⚠ same condition
KRT1 p.Gly556Ser Uncertain significance ★★ ⚠ same condition
KRT1 c.1511-11T>C Benign/Likely benign ★★ same condition
KRT1 c.592-8G>A Benign/Likely benign ★★ same condition
KRT1 c.*344C>T 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/krt1-p-ile25 (accessed [today's date]).

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