Is KDM5A p.Phe130Ser (c.389T>C) pathogenic?

KDM5A p.Phe130Ser (c.389T>C) is classified Uncertain significance in KDM5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). AlphaMissense: likely pathogenic (0.9468); Very rare (popmax 8.47e-05%, nfe).

How common is KDM5A p.Phe130Ser (c.389T>C) in the general population?

KDM5A p.Phe130Ser (c.389T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KDM5A p.Phe130Ser (c.389T>C)?

AlphaMissense predicts likely pathogenic (score 0.9468) — an in-silico prediction, not a clinical call.

KDM5A p.Phe130Ser

c.389T>C · VCV4042329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9468 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9468	likely pathogenic
REVEL	0.742	pathogenic-leaning
SaProt	LLR -10.11	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 9.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 26 kb · p 7.3e-05 · regional, not allelic
Overall
CADD	28.0	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 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.84e-05% 1/1,461,750 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.Phe130Ser
Coding: c.389T>C
MANE Select: NM_001042603
Type: single nucleotide variant
Location: chr12:366082 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.98 · 46 PDB
Residue 130: the arid domain; an α-helix

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

Similar variants

KDM5A c.4074+1G>A Likely pathogenic ★★ same type
KDM5A p.Ala1260Val Uncertain significance ★★ ⚠ same type
KDM5A p.Ala736Thr Uncertain significance ★★ ⚠ same type
KDM5A p.Glu1021Gly Uncertain significance ★★ ⚠ same type
KDM5A p.Gly630Glu Uncertain significance ★★ ⚠ same type
KDM5A p.Ile1011Thr Uncertain significance ★★ ⚠ same type
KDM5A p.Ser479Cys Uncertain significance ★★ ⚠ same type
KDM5A p.Ser572Cys Uncertain significance ★★ ⚠ same type

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-phe130ser (accessed [today's date]).

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