Is KDM4E p.Pro206Ala (c.616C>G) pathogenic?

KDM4E p.Pro206Ala (c.616C>G) is classified Uncertain significance in KDM4E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely benign (0.1824); Ultra-rare (popmax 0.0339%, nfe).

How common is KDM4E p.Pro206Ala (c.616C>G) in the general population?

KDM4E p.Pro206Ala (c.616C>G) is ultra-rare (popmax 0.0339%, nfe) (gnomAD).

What do computational predictors say about KDM4E p.Pro206Ala (c.616C>G)?

AlphaMissense predicts likely benign (score 0.1824) — an in-silico prediction, not a clinical call.

KDM4E p.Pro206Ala

c.616C>G · rs367581440 · VCV2342163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1824	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -10.81	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 4.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 677 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	22.2	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 0.0339% European (non-Finnish) · 400/1,180,030 alleles

Filtering AF 0.0311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.03%

Overall 0.0268% 433/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0339%	2,950
Remaining individualsnot grpmax-eligible	0.0304%	3,289
South Asian	0.00988%	10,120
Admixed American	0.00333%	30,004
African / African-American	0.00267%	37,454
East Asian	0.00223%	44,896

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.Pro206Ala
Coding: c.616C>G
MANE Select: NM_001161630
dbSNP: rs367581440
Type: single nucleotide variant
Location: chr11:95026173 (GRCh38)
Structure: AlphaFold pLDDT 76.85 · 1 PDB
Residue 206: the jmjc domain

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

Similar variants

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
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-pro206ala (accessed [today's date]).

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