Is KDM2B p.Cys646fs (c.1936dup) pathogenic?

KDM2B p.Cys646fs (c.1936dup) is classified Likely pathogenic in KDM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-16). Associated with neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities.

KDM2B p.Cys646fs

Q: What condition is associated with KDM2B p.Cys646fs (c.1936dup)?

KDM2B p.Cys646fs (c.1936dup) is associated with neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities (ClinVar).

c.1936dup · VCV4795799

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 13 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1

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

Variant & gene context

Gene: KDM2B
Protein: p.Cys646fs
Coding: c.1936dup
MANE Select: NM_032590
Type: Duplication
Location: chr12:121453142 (GRCh38)
Gene constraint: LOEUF 0.266 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.20 · 4 PDB
Residue 646: a binding site; a UniProt-annotated variant site (in nedcro; likely pathogenic)

Full KDM2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM2B p.Cys616Arg Pathogenic/Likely pathogenic ★★ same condition
KDM2B p.Gly638Asp Pathogenic ★★ same condition
KDM2B p.Gly638Ser Pathogenic ★ same condition
KDM2B p.Gly638Val Likely pathogenic ★ same condition
KDM2B p.His253Arg Likely pathogenic ★ same condition
KDM2B p.Cys616Tyr Uncertain significance ★ ⚠ same condition
KDM2B c.1903_1905AAG Pathogenic same condition
KDM2B p.Cys630Ser Pathogenic 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/kdm2b-p-cys646fs (accessed [today's date]).

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