Is KDM5C p.Pro480Leu (c.1439C>T) pathogenic?

KDM5C p.Pro480Leu (c.1439C>T) is classified Pathogenic in KDM5C (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.000112%, nfe); Associated with syndromic X-linked intellectual disability Claes-Jensen type.

What condition is associated with KDM5C p.Pro480Leu (c.1439C>T)?

KDM5C p.Pro480Leu (c.1439C>T) is associated with syndromic X-linked intellectual disability Claes-Jensen type (ClinVar).

How common is KDM5C p.Pro480Leu (c.1439C>T) in the general population?

KDM5C p.Pro480Leu (c.1439C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about KDM5C p.Pro480Leu (c.1439C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

KDM5C p.Pro480Leu

c.1439C>T · rs1057518697 · VCV374324

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Claes-Jensen type

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic ✓ concordant with ClinVar
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -15.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.50 · evaluated, not missing
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	26.1	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 0.000112% European (non-Finnish) · 1/895,177 alleles

Overall 9.11e-05% 1/1,097,861 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.Pro480Leu
Coding: c.1439C>T
MANE Select: NM_004187
dbSNP: rs1057518697
Type: single nucleotide variant
Location: chrX:53210820 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 480: the jmjc domain; a UniProt-annotated variant site (in mrxscj; patient fibroblasts show decreased enzymatic activity); an α-helix

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

Disease context

syndromic X-linked intellectual disability Claes-Jensen type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Pro480= Uncertain significance ★ same residue
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.Arg828Ter Pathogenic ★★ same condition
KDM5C p.Arg943Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Gln1020Ter 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-pro480leu (accessed [today's date]).

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