Is KDM4E p.Leu227Pro (c.680T>C) pathogenic?

KDM4E p.Leu227Pro (c.680T>C) is classified Uncertain significance in KDM4E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.7955); Ultra-rare (popmax 0.0869%, eas).

How common is KDM4E p.Leu227Pro (c.680T>C) in the general population?

KDM4E p.Leu227Pro (c.680T>C) is ultra-rare (popmax 0.0869%, eas) (gnomAD).

What do computational predictors say about KDM4E p.Leu227Pro (c.680T>C)?

AlphaMissense predicts likely pathogenic (score 0.7955) — an in-silico prediction, not a clinical call.

KDM4E p.Leu227Pro

c.680T>C · VCV4091295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7955	likely pathogenic · top 8% in KDM4E
REVEL	0.523	indeterminate
SaProt	LLR -12.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 0.64
Regional constraint	o/e 1.03	unconstrained · MANE · 839 bp · p 0.58 · regional, not allelic
Overall
CADD	22.2	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 0.0869% East Asian · 39/44,876 alleles

Filtering AF 0.0653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00551% 89/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0869%	1,151
South Asian	0.0209%	4,793
Remaining individualsnot grpmax-eligible	0.0128%	7,814
European (non-Finnish)	0.00186%	53,636
Finnishnot grpmax-eligible	0.00156%	64,008

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: KDM4E
Protein: p.Leu227Pro
Coding: c.680T>C
MANE Select: NM_001161630
Type: single nucleotide variant
Location: chr11:95026237 (GRCh38)
Structure: AlphaFold pLDDT 76.85 · 1 PDB
Residue 227: the jmjc domain; an α-helix

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

Similar variants

KDM4E p.Leu227Phe 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-leu227pro (accessed [today's date]).

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