Is KDM5B p.Pro68Thr (c.202C>A) pathogenic?

KDM5B p.Pro68Thr (c.202C>A) is classified Uncertain significance in KDM5B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1081); Ultra-rare (popmax 0.0167%, amr); Associated with intellectual disability, autosomal recessive 65.

What condition is associated with KDM5B p.Pro68Thr (c.202C>A)?

KDM5B p.Pro68Thr (c.202C>A) is associated with intellectual disability, autosomal recessive 65 (ClinVar).

How common is KDM5B p.Pro68Thr (c.202C>A) in the general population?

KDM5B p.Pro68Thr (c.202C>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about KDM5B p.Pro68Thr (c.202C>A)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

KDM5B p.Pro68Thr

c.202C>A · rs369444528 · VCV845733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal recessive 65

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -8.87	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 6.8	GERP -3.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 46 kb · p 0.3 · regional, not allelic
Overall
CADD	24.0	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 0.0167% Admixed American · 10/59,818 alleles

Filtering AF 0.00902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.00323% 52/1,610,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0417%	2,398
Admixed Americangrpmax	0.0167%	5,982
East Asian	0.0112%	8,924
African / African-American	0.00134%	74,536
South Asian	0.00111%	90,492
European (non-Finnish)	0.000764%	130,957

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro68Thr
Coding: c.202C>A
MANE Select: NM_006618
dbSNP: rs369444528
Type: single nucleotide variant
Location: chr1:202808104 (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 68: the jmjn domain

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

Disease context

intellectual disability, autosomal recessive 65 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5B c.2945+1G>A Likely pathogenic ★★ same condition
KDM5B p.Arg1047Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5B p.Arg1214Ter Likely pathogenic ★★ same condition
KDM5B p.Arg1426Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5B p.Arg299Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5B p.Arg441Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5B p.Arg570Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5B p.Arg98Cys 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/kdm5b-p-pro68thr (accessed [today's date]).

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