Is KDM5B p.Pro281Ser (c.841C>T) pathogenic?

KDM5B p.Pro281Ser (c.841C>T) is classified Uncertain significance in KDM5B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.0871); Ultra-rare (popmax 0.0115%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KDM5B p.Pro281Ser (c.841C>T)?

KDM5B p.Pro281Ser (c.841C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KDM5B p.Pro281Ser (c.841C>T) in the general population?

KDM5B p.Pro281Ser (c.841C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about KDM5B p.Pro281Ser (c.841C>T)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

KDM5B p.Pro281Ser

c.841C>T · rs767569381 · VCV2514662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -6.79	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 4.1	GERP 0.95, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 46 kb · p 0.3 · regional, not allelic
Overall
CADD	19.81	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 0.0115% European (non-Finnish) · 135/1,176,066 alleles

Filtering AF 0.00989% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00924%

Overall 0.00888% 143/1,609,488 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,712
Remaining individualsnot grpmax-eligible	0.00962%	10,394
Admixed American	0.00167%	59,966
African / African-American	0.00134%	74,782

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.Pro281Ser
Coding: c.841C>T
MANE Select: NM_006618
dbSNP: rs767569381
Type: single nucleotide variant
Location: chr1:202762776 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.52 · 56 PDB

Full KDM5B 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

KDM5B p.Pro281Ala Uncertain significance ★ ⚠ same residue
KDM5B p.Pro281Arg Uncertain significance ★ ⚠ same residue
KDM5B p.Ala747Thr Uncertain significance ★★ ⚠ same condition
KDM5B p.Arg619His Uncertain significance ★★ ⚠ same condition
KDM5B p.Arg733Trp Uncertain significance ★★ ⚠ same condition
KDM5B p.Arg827Gln Uncertain significance ★★ ⚠ same condition
KDM5B p.Arg843Gln Uncertain significance ★★ ⚠ same condition
KDM5B p.Arg843Trp 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-pro281ser (accessed [today's date]).

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