Is KRT9 p.Arg374Trp (c.1120C>T) pathogenic?

KRT9 p.Arg374Trp (c.1120C>T) is classified Conflicting classifications of pathogenicity in KRT9 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.345); Rare (popmax 0.275%, nfe); Associated with palmoplantar keratoderma, epidermolytic.

What condition is associated with KRT9 p.Arg374Trp (c.1120C>T)?

KRT9 p.Arg374Trp (c.1120C>T) is associated with palmoplantar keratoderma, epidermolytic (ClinVar).

How common is KRT9 p.Arg374Trp (c.1120C>T) in the general population?

KRT9 p.Arg374Trp (c.1120C>T) is rare (popmax 0.275%, nfe) (gnomAD).

What do computational predictors say about KRT9 p.Arg374Trp (c.1120C>T)?

AlphaMissense predicts ambiguous (score 0.345) — an in-silico prediction, not a clinical call.

KRT9 p.Arg374Trp

c.1120C>T · rs116216460 · VCV891760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.345 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.275%, nfe)

Conditions

palmoplantar keratoderma, epidermolytic

Computational evidence

Protein change
AlphaMissense	0.345	ambiguous
REVEL	0.383	indeterminate
SaProt	LLR -10.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.4, phastCons 0.009
Regional constraint	o/e 0.90	unconstrained · MANE · 4,200 bp · p 0.017 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.275% European (non-Finnish) · 3,244/1,180,028 alleles

Filtering AF 0.267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.264%

Overall 0.234% 3,780/1,614,030 alleles · rare exomes 3,572/1,461,882 · genomes 208/152,148 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.804%	124
Remaining individualsnot grpmax-eligible	0.306%	327
European (non-Finnish)grpmax	0.275%	364
Admixed American	0.0667%	1,500
African / African-American	0.0481%	2,080
East Asian	0.0223%	4,490
South Asian	0.0176%	5,693
Middle Eastern	0.0164%	6,084
Finnishnot grpmax-eligible	0.00625%	16,008

Ashkenazi Jewish 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: KRT9
Protein: p.Arg374Trp
Coding: c.1120C>T
MANE Select: NM_000226
dbSNP: rs116216460
Type: single nucleotide variant
Location: chr17:41568558 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43
Residue 374: 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.Arg374Gln Uncertain significance ★ ⚠ same residue
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

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-arg374trp (accessed [today's date]).

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