Is KDM5A p.Ile1226Val (c.3676A>G) pathogenic?

KDM5A p.Ile1226Val (c.3676A>G) is classified Uncertain significance in KDM5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: ambiguous (0.4846); Ultra-rare (popmax 0.0165%, sas).

How common is KDM5A p.Ile1226Val (c.3676A>G) in the general population?

KDM5A p.Ile1226Val (c.3676A>G) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about KDM5A p.Ile1226Val (c.3676A>G)?

AlphaMissense predicts ambiguous (score 0.4846) — an in-silico prediction, not a clinical call.

KDM5A p.Ile1226Val

c.3676A>G · VCV4042325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4846	ambiguous
REVEL	0.207	benign-leaning
SaProt	LLR -4.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 30 kb · p 0.0032 · regional, not allelic
Overall
CADD	23.8	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 0.0165% South Asian · 15/91,086 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00607% 98/1,614,176 alleles · ultra-rare exomes 89/1,461,882 · genomes 9/152,294 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,072
East Asian	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00568%	17,612
Admixed American	0.00333%	30,008

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.Ile1226Val
Coding: c.3676A>G
MANE Select: NM_001042603
Type: single nucleotide variant
Location: chr12:307708 (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-ile1226val (accessed [today's date]).

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