Is KRT9 p.His375= (c.1125C>T) pathogenic?

KRT9 p.His375= (c.1125C>T) is classified Conflicting classifications of pathogenicity in KRT9 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-24). Rare (popmax 0.187%, afr); Associated with palmoplantar keratoderma, epidermolytic.

What condition is associated with KRT9 p.His375= (c.1125C>T)?

KRT9 p.His375= (c.1125C>T) is associated with palmoplantar keratoderma, epidermolytic (ClinVar).

How common is KRT9 p.His375= (c.1125C>T) in the general population?

KRT9 p.His375= (c.1125C>T) is rare (popmax 0.187%, afr) (gnomAD).

KRT9 p.His375=

c.1125C>T · rs114867228 · VCV323127

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.187%, afr)

Conditions

palmoplantar keratoderma, epidermolytic

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 -0.77	GERP -4.2
Overall
CADD	0.954	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.187% African / African-American · 140/75,026 alleles

Filtering AF 0.161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.152%

Overall 0.13% 2,099/1,614,156 alleles · rare exomes 1,888/1,461,878 · genomes 211/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.187%	536
European (non-Finnish)	0.148%	674
Remaining individualsnot grpmax-eligible	0.131%	762
Admixed American	0.105%	953
Middle Eastern	0.0825%	1,212
Finnishnot grpmax-eligible	0.0656%	1,525
South Asian	0.0154%	6,506
East Asian	0.00668%	14,961

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: KRT9
Protein: p.His375=
Coding: c.1125C>T
MANE Select: NM_000226
dbSNP: rs114867228
Type: single nucleotide variant
Location: chr17:41568553 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43
Residue 375: the if rod domain; the 'coil 2' region

Full KRT9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

KRT9 p.Arg163Gln Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Arg163Trp Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Asn161Lys Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Gly116Asp Uncertain significance ★★ ⚠ same condition
KRT9 p.Gly193Glu Uncertain significance ★★ ⚠ same condition
KRT9 p.Gly507Arg Uncertain significance ★★ same condition
KRT9 p.Gly507Val Uncertain significance ★★ ⚠ same condition
KRT9 p.Ile341Val 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/krt9-p-his375 (accessed [today's date]).

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