Is KDM4E p.Arg99His (c.296G>A) pathogenic?

KDM4E p.Arg99His (c.296G>A) is classified Uncertain significance in KDM4E (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-30). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.0781%, afr).

How common is KDM4E p.Arg99His (c.296G>A) in the general population?

KDM4E p.Arg99His (c.296G>A) is ultra-rare (popmax 0.0781%, afr) (gnomAD).

What do computational predictors say about KDM4E p.Arg99His (c.296G>A)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

KDM4E p.Arg99His

c.296G>A · rs568507965 · VCV2358610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0781%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.55	GERP -3.8
Regional constraint	o/e 0.73	unconstrained · MANE · 677 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	10.67	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 0.0781% African / African-American · 58/74,300 alleles

Filtering AF 0.0619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.0067% 107/1,595,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0781%	1,281
East Asian	0.0249%	4,019
Middle Eastern	0.0165%	6,054
Admixed American	0.00846%	11,827
Remaining individualsnot grpmax-eligible	0.00644%	15,535
European (non-Finnish)	0.00229%	43,579
South Asian	0.00111%	89,962

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: KDM4E
Protein: p.Arg99His
Coding: c.296G>A
MANE Select: NM_001161630
dbSNP: rs568507965
Type: single nucleotide variant
Location: chr11:95025853 (GRCh38)
Structure: AlphaFold pLDDT 76.85 · 1 PDB
Residue 99: an α-helix

Full KDM4E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KDM4E p.Arg99Cys Uncertain significance ★ ⚠ same residue
KDM4E p.Ala187= Likely benign ★★ same type
KDM4E p.Cys381Tyr Benign ★★ same type
KDM4E p.Gln42Arg Benign ★★ same type
KDM4E p.Thr190= Likely benign ★★ same type
KDM4E p.Ala224Asp Uncertain significance ★ ⚠ same type
KDM4E p.Ala265Val Uncertain significance ★ ⚠ same type
KDM4E p.Ala287Thr 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/kdm4e-p-arg99his (accessed [today's date]).

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