Is KDM5C p.Pro15Arg (c.44C>G) pathogenic?

KDM5C p.Pro15Arg (c.44C>G) is classified Uncertain significance in KDM5C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9316); Absent from gnomAD v4.1; Associated with Spastic paraplegia.

What condition is associated with KDM5C p.Pro15Arg (c.44C>G)?

KDM5C p.Pro15Arg (c.44C>G) is associated with Spastic paraplegia (ClinVar).

How common is KDM5C p.Pro15Arg (c.44C>G) in the general population?

KDM5C p.Pro15Arg (c.44C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KDM5C p.Pro15Arg (c.44C>G)?

AlphaMissense predicts likely pathogenic (score 0.9316) — an in-silico prediction, not a clinical call.

KDM5C p.Pro15Arg

c.44C>G · VCV4072520

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9316 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9316	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -15.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 125 bp · p 0.0003 · regional, not allelic
Overall
CADD	26.1	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

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: KDM5C
Protein: p.Pro15Arg
Coding: c.44C>G
MANE Select: NM_004187
Type: single nucleotide variant
Location: chrX:53224846 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 15: the jmjn domain

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

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Pro15Leu Uncertain significance ★ ⚠ same residue
KDM5C p.Pro15= Benign/Likely benign ★★ same residue
KDM5C c.1243-2A>G Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg681Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg750Trp Likely pathogenic ★★ same condition
KDM5C p.Arg778Ter Pathogenic ★★ same condition
KDM5C p.Gln588Ter Pathogenic ★★ same condition
KDM5C c.4038+6C>G 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-pro15arg (accessed [today's date]).

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