Is KDM5A p.Phe477Val (c.1429T>G) pathogenic?

KDM5A p.Phe477Val (c.1429T>G) is classified Pathogenic in KDM5A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-09). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 8.47e-05%, nfe); Associated with El Hayek-Chahrour neurodevelopmental disorder.

What condition is associated with KDM5A p.Phe477Val (c.1429T>G)?

KDM5A p.Phe477Val (c.1429T>G) is associated with El Hayek-Chahrour neurodevelopmental disorder (ClinVar).

How common is KDM5A p.Phe477Val (c.1429T>G) in the general population?

KDM5A p.Phe477Val (c.1429T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KDM5A p.Phe477Val (c.1429T>G)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

KDM5A p.Phe477Val

c.1429T>G · rs2498285184 · VCV3235141

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

El Hayek-Chahrour neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 7% in KDM5A
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -14.51	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 22 kb · p 4.4e-08 · regional, not allelic
Overall
CADD	27.6	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 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 6.84e-05% 1/1,461,830 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: KDM5A
Protein: p.Phe477Val
Coding: c.1429T>G
MANE Select: NM_001042603
dbSNP: rs2498285184
Type: single nucleotide variant
Location: chr12:334302 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.98 · 46 PDB
Residue 477: the jmjc domain; a UniProt-annotated variant site (in nedehc; uncertain significance; decreased protein expression levels)

Full KDM5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

El Hayek-Chahrour neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5A p.Phe477Leu Uncertain significance ⚠ same residue
KDM5A c.4074+1G>A Likely pathogenic ★★ same condition
KDM5A p.Ile1011Thr Uncertain significance ★★ ⚠ same condition
KDM5A p.Gln832Ter Pathogenic ★ same condition
KDM5A p.Arg1350Ter Conflicting classifications of pathogenicity ★ same condition
KDM5A p.Gln576Ter Uncertain significance ★ same condition
KDM5A c.2541+1G>T Pathogenic same condition
KDM5A c.166-6_169del Likely 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/kdm5a-p-phe477val (accessed [today's date]).

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