Is KDM5A p.Arg271Ser (c.813G>C) pathogenic?

KDM5A p.Arg271Ser (c.813G>C) is classified Uncertain significance in KDM5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.3016); Very rare (popmax 0.00167%, amr).

How common is KDM5A p.Arg271Ser (c.813G>C) in the general population?

KDM5A p.Arg271Ser (c.813G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KDM5A p.Arg271Ser (c.813G>C)?

AlphaMissense predicts likely benign (score 0.3016) — an in-silico prediction, not a clinical call.

KDM5A p.Arg271Ser

c.813G>C · VCV4091336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3016 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3016	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -5.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 8,831 bp · p 0.38 · regional, not allelic
Overall
CADD	19.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/60,028 alleles

Overall 6.85e-05% 1/1,460,694 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.Arg271Ser
Coding: c.813G>C
MANE Select: NM_001042603
Type: single nucleotide variant
Location: chr12:355215 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.98 · 46 PDB

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-arg271ser (accessed [today's date]).

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