Is KDM5C p.Arg367Trp (c.1099C>T) pathogenic?

KDM5C p.Arg367Trp (c.1099C>T) is classified Uncertain significance in KDM5C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.8911); Very rare (popmax 0.000224%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KDM5C p.Arg367Trp (c.1099C>T)?

KDM5C p.Arg367Trp (c.1099C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KDM5C p.Arg367Trp (c.1099C>T) in the general population?

KDM5C p.Arg367Trp (c.1099C>T) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about KDM5C p.Arg367Trp (c.1099C>T)?

AlphaMissense predicts likely pathogenic (score 0.8911) — an in-silico prediction, not a clinical call.

KDM5C p.Arg367Trp

c.1099C>T · rs2073692420 · VCV2254684

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8911	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -15.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.95, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 4,253 bp · p 4.1e-05 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.000224% European (non-Finnish) · 2/894,565 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000182% 2/1,096,215 alleles · very rare

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: KDM5C
Protein: p.Arg367Trp
Coding: c.1099C>T
MANE Select: NM_004187
dbSNP: rs2073692420
Type: single nucleotide variant
Location: chrX:53214712 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB

Full KDM5C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Arg367Gln Uncertain significance ★ ⚠ same residue
KDM5C p.Arg68Ter Pathogenic ★★ same condition
KDM5C p.Gln1020Ter Pathogenic ★★ same condition
KDM5C p.Gln859Ter Pathogenic ★★ same condition
KDM5C p.Glu698Lys Likely pathogenic ★★ same condition
KDM5C p.Arg909Trp Uncertain significance ★★ ⚠ same condition
KDM5C p.Gln859Lys Uncertain significance ★★ ⚠ same condition
KDM5C p.Glu1276Lys 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/kdm5c-p-arg367trp (accessed [today's date]).

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