Is KDM4E p.Gln42Pro (c.125A>C) pathogenic?

KDM4E p.Gln42Pro (c.125A>C) is classified Uncertain significance in KDM4E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.4337); Very rare (popmax 0.00137%, afr).

How common is KDM4E p.Gln42Pro (c.125A>C) in the general population?

KDM4E p.Gln42Pro (c.125A>C) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about KDM4E p.Gln42Pro (c.125A>C)?

AlphaMissense predicts ambiguous (score 0.4337) — an in-silico prediction, not a clinical call.

KDM4E p.Gln42Pro

c.125A>C · VCV4543072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4337	ambiguous
REVEL	0.1	moderately benign-leaning
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.8
Regional constraint	o/e 0.73	unconstrained · MANE · 677 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	9.665	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 0.00137% African / African-American · 1/72,962 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000323% 5/1,548,938 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,480
African / African-Americangrpmax	0.00137%	72,962
European (non-Finnish)	0.00026%	384,073

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln42Pro
Coding: c.125A>C
MANE Select: NM_001161630
Type: single nucleotide variant
Location: chr11:95025682 (GRCh38)
Structure: AlphaFold pLDDT 76.85 · 1 PDB
Residue 42: the jmjn domain; a UniProt-annotated variant site (in); an α-helix

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

Similar variants

KDM4E p.Gln42Arg Benign ★★ same residue
KDM4E p.Ala187= Likely benign ★★ same type
KDM4E p.Cys381Tyr 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
KDM4E p.Ala406Thr 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-gln42pro (accessed [today's date]).

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