Is KDM4D p.Arg102Cys (c.304C>T) pathogenic?

KDM4D p.Arg102Cys (c.304C>T) is classified Uncertain significance in KDM4D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.0164%, mid).

How common is KDM4D p.Arg102Cys (c.304C>T) in the general population?

KDM4D p.Arg102Cys (c.304C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about KDM4D p.Arg102Cys (c.304C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

KDM4D p.Arg102Cys

c.304C>T · VCV3533127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP 0.2
Regional constraint	o/e 0.44	unconstrained · MANE · 358 bp · p 9.3e-12 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000496% 8/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0022%	45,545
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000339%	295,009

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.Arg102Cys
Coding: c.304C>T
MANE Select: NM_018039
Type: single nucleotide variant
Location: chr11:94997676 (GRCh38)
Gene constraint: LOEUF 1.728 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 74.40 · 284 PDB
Residue 102: 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.Arg225Cys Uncertain significance ★ ⚠ same type
KDM4D p.Arg225His Uncertain significance ★ ⚠ same type
KDM4D p.Arg236Trp Uncertain significance ★ ⚠ same type
KDM4D p.Arg263Leu 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-arg102cys (accessed [today's date]).

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