Is KDM4D p.Ser40Phe (c.119C>T) pathogenic?

KDM4D p.Ser40Phe (c.119C>T) is classified Uncertain significance in KDM4D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.2104); Very rare (popmax 0.00267%, afr).

How common is KDM4D p.Ser40Phe (c.119C>T) in the general population?

KDM4D p.Ser40Phe (c.119C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about KDM4D p.Ser40Phe (c.119C>T)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

KDM4D p.Ser40Phe

c.119C>T · VCV4091291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -12.09	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 4.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 210 bp · p 0.016 · regional, not allelic
Overall
CADD	27.2	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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,950 alleles · very rare

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: KDM4D
Protein: p.Ser40Phe
Coding: c.119C>T
MANE Select: NM_018039
Type: single nucleotide variant
Location: chr11:94997491 (GRCh38)
Gene constraint: LOEUF 1.728 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 74.40 · 284 PDB
Residue 40: the jmjn domain; an α-helix

Full KDM4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KDM4D p.Ala471Ser Benign ★★ same type
KDM4D p.Ser355Arg Benign ★★ same type
KDM4D p.Ala315Ser Uncertain significance ★ ⚠ same type
KDM4D p.Ala8Ser Uncertain significance ★ ⚠ same type
KDM4D p.Arg102Cys Uncertain significance ★ ⚠ same type
KDM4D p.Arg225Cys Uncertain significance ★ ⚠ same type
KDM4D p.Arg225His Uncertain significance ★ ⚠ same type
KDM4D p.Arg236Trp 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/kdm4d-p-ser40phe (accessed [today's date]).

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