Is KDM4B p.Pro425Leu (c.1274C>T) pathogenic?

KDM4B p.Pro425Leu (c.1274C>T) is classified Uncertain significance in KDM4B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0651); Ultra-rare (popmax 0.0325%, sas); Associated with Inborn genetic diseases.

What condition is associated with KDM4B p.Pro425Leu (c.1274C>T)?

KDM4B p.Pro425Leu (c.1274C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KDM4B p.Pro425Leu (c.1274C>T) in the general population?

KDM4B p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0325%, sas) (gnomAD).

What do computational predictors say about KDM4B p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

KDM4B p.Pro425Leu

c.1274C>T · VCV3533089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.75	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 -1.2	GERP -1.4
Regional constraint	o/e 1.06	unconstrained · MANE · 21 kb · p 0.26 · regional, not allelic
Overall
CADD	8.864	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 0.0325% South Asian · 27/83,040 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00492% 76/1,543,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0325%	3,076
African / African-American	0.0247%	4,055
Admixed American	0.00998%	10,023
Finnishnot grpmax-eligible	0.00516%	19,395
East Asian	0.00245%	40,886
European (non-Finnish)	0.00184%	54,486
Remaining individualsnot grpmax-eligible	0.00167%	59,702

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: KDM4B
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_015015
Type: single nucleotide variant
Location: chr19:5119811 (GRCh38)
Gene constraint: LOEUF 0.371 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.50 · 6 PDB
Residue 425: the 'disordered' region

Full KDM4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM4B c.432+1G>A Pathogenic/Likely pathogenic ★★ same condition
KDM4B p.His768Arg Likely pathogenic ★★ same condition
KDM4B p.Ala187Thr Uncertain significance ★★ ⚠ same condition
KDM4B p.Ala759Thr Uncertain significance ★★ ⚠ same condition
KDM4B p.Arg1020His Uncertain significance ★★ ⚠ same condition
KDM4B p.Arg1035Cys Uncertain significance ★★ ⚠ same condition
KDM4B p.Arg57Trp Uncertain significance ★★ ⚠ same condition
KDM4B p.Arg828Cys Uncertain significance ★★ ⚠ same condition

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/kdm4b-p-pro425leu (accessed [today's date]).

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