Is KRT9 p.Ser599Arg (c.1795A>C) pathogenic?

KRT9 p.Ser599Arg (c.1795A>C) is classified Uncertain significance in KRT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely benign (0.2925); Absent from gnomAD v4.1; Associated with epidermolytic palmoplantar keratoderma, 1.

What condition is associated with KRT9 p.Ser599Arg (c.1795A>C)?

KRT9 p.Ser599Arg (c.1795A>C) is associated with epidermolytic palmoplantar keratoderma, 1 (ClinVar).

How common is KRT9 p.Ser599Arg (c.1795A>C) in the general population?

KRT9 p.Ser599Arg (c.1795A>C) is absent from gnomAD v4.1 (gnomAD).

How is Epidermolytic palmoplantar keratoderma inherited?

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

What do computational predictors say about KRT9 p.Ser599Arg (c.1795A>C)?

AlphaMissense predicts likely benign (score 0.2925) — an in-silico prediction, not a clinical call.

KRT9 p.Ser599Arg

c.1795A>C · VCV3581942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2925 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermolytic palmoplantar keratoderma, 1

Computational evidence

Protein change
AlphaMissense	0.2925	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -0.91
Regional constraint	o/e 0.90	unconstrained · MANE · 4,200 bp · p 0.017 · regional, not allelic
Overall
CADD	14.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KRT9
Protein: p.Ser599Arg
Coding: c.1795A>C
MANE Select: NM_000226
Type: single nucleotide variant
Location: chr17:41567350 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43
Residue 599: the 'disordered' region; the 'tail' region

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

Disease context

epidermolytic palmoplantar keratoderma, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epidermolytic palmoplantar keratoderma (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Ireland)

Similar variants

KRT9 p.Ser599= Uncertain significance ★ same residue
KRT9 p.Arg163Gln Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Arg163Leu Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Arg163Trp Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Asn161Lys Pathogenic/Likely pathogenic ★★ same condition
KRT9 p.Asn161Ser Pathogenic ★★ same condition
KRT9 p.Met157Val Pathogenic ★★ same condition
KRT9 p.Arg327His 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-ser599arg (accessed [today's date]).

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