Is KDM5C p.Pro598Arg (c.1793C>G) pathogenic?

KDM5C p.Pro598Arg (c.1793C>G) is classified Conflicting classifications of pathogenicity in KDM5C (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-22). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 0.00296%, eas); Associated with Spastic paraplegia.

What condition is associated with KDM5C p.Pro598Arg (c.1793C>G)?

KDM5C p.Pro598Arg (c.1793C>G) is associated with Spastic paraplegia, syndromic X-linked intellectual disability Claes-Jensen type (ClinVar).

How common is KDM5C p.Pro598Arg (c.1793C>G) in the general population?

KDM5C p.Pro598Arg (c.1793C>G) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about KDM5C p.Pro598Arg (c.1793C>G)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

KDM5C p.Pro598Arg

c.1793C>G · rs1556842216 · VCV1720027

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 8% in KDM5C
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -14.80	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 10 kb · p 1.4e-30 · regional, not allelic
Overall
CADD	22.4	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 0.00296% East Asian · 1/33,806 alleles

Overall 0.00089% 1/112,298 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.Pro598Arg
Coding: c.1793C>G
MANE Select: NM_004187
dbSNP: rs1556842216
Type: single nucleotide variant
Location: chrX:53201927 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 598: the jmjc 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

Also linked: syndromic X-linked intellectual disability Claes-Jensen type

Similar variants

KDM5C p.Pro598= Benign/Likely benign ★★ same residue
KDM5C p.Pro598Leu Likely pathogenic same residue
KDM5C c.1243-2A>G Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg332Ter Pathogenic ★★ same condition
KDM5C p.Arg599Cys 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

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-pro598arg (accessed [today's date]).

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