Is CUX2 p.Pro994= (c.2982T>G) pathogenic?

CUX2 p.Pro994= (c.2982T>G) is classified Likely benign in CUX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-02-24). Very rare (popmax 0.000192%, nfe); Associated with CUX2-related disorder.

What condition is associated with CUX2 p.Pro994= (c.2982T>G)?

CUX2 p.Pro994= (c.2982T>G) is associated with CUX2-related disorder (ClinVar).

How common is CUX2 p.Pro994= (c.2982T>G) in the general population?

CUX2 p.Pro994= (c.2982T>G) is very rare (popmax 0.000192%, nfe) (gnomAD).

CUX2 p.Pro994=

c.2982T>G · rs2499909656 · VCV3051876

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000192%, nfe)

Conditions

CUX2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.4
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000192% European (non-Finnish) · 2/1,039,966 alleles

Filtering AF 3.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000154% 2/1,295,724 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: CUX2
Protein: p.Pro994=
Coding: c.2982T>G
MANE Select: NM_015267
dbSNP: rs2499909656
Type: single nucleotide variant
Location: chr12:111334496 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 994: the 'disordered' region

Full CUX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CUX2-related disorder

Similar variants

CUX2 p.Pro727Leu Uncertain significance ★★ ⚠ same condition
CUX2 c.560+2T>C Uncertain significance ★ same condition
CUX2 p.Arg225Gln Uncertain significance ★ ⚠ same condition
CUX2 p.Pro1089Ser Likely pathogenic same condition
CUX2 p.Asp237Glu Uncertain significance ⚠ same condition
CUX2 p.Thr875Ala Uncertain significance ⚠ same condition
CUX2 c.63+9G>C Likely benign same condition
CUX2 c.637+10G>A Likely benign 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/cux2-p-pro994 (accessed [today's date]).

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