Is KDM5B p.Phe596Ser (c.1787T>C) pathogenic?

KDM5B p.Phe596Ser (c.1787T>C) is classified Uncertain significance in KDM5B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-15). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 8.48e-05%, nfe).

How common is KDM5B p.Phe596Ser (c.1787T>C) in the general population?

KDM5B p.Phe596Ser (c.1787T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about KDM5B p.Phe596Ser (c.1787T>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

KDM5B p.Phe596Ser

c.1787T>C · rs1419662430 · VCV1710764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 5% in KDM5B
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -11.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 27 kb · p 0.42 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 6.84e-05% 1/1,461,742 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: KDM5B
Protein: p.Phe596Ser
Coding: c.1787T>C
MANE Select: NM_006618
dbSNP: rs1419662430
Type: single nucleotide variant
Location: chr1:202750693 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 56 PDB
Residue 596: a β-strand; the jmjc domain; a UniProt-annotated variant site (in mrt65)

Full KDM5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KDM5B c.2945+1G>A Likely pathogenic ★★ same type
KDM5B p.Arg1047Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg1214Ter Likely pathogenic ★★ same type
KDM5B p.Arg1253Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg1281Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg1426Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg259Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg299Ter Pathogenic/Likely pathogenic ★★ 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/kdm5b-p-phe596ser (accessed [today's date]).

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