Is KDM5B p.Arg259Ter (c.775C>T) pathogenic?

KDM5B p.Arg259Ter (c.775C>T) is classified Pathogenic/Likely pathogenic in KDM5B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-27). Very rare (popmax 0.000257%, nfe).

How common is KDM5B p.Arg259Ter (c.775C>T) in the general population?

KDM5B p.Arg259Ter (c.775C>T) is very rare (popmax 0.000257%, nfe) (gnomAD).

KDM5B p.Arg259Ter

c.775C>T · rs776299767 · VCV1690558

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000257% European (non-Finnish) · 3/1,165,476 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00021% 3/1,428,986 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.Arg259Ter
Coding: c.775C>T
MANE Select: NM_006618
dbSNP: rs776299767
Type: single nucleotide variant
Location: chr1:202764082 (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

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.Arg299Ter Pathogenic/Likely pathogenic ★★ same type
KDM5B p.Arg441Ter 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-arg259ter (accessed [today's date]).

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