Is CUX2 p.Ser584= (c.1752G>A) pathogenic?

CUX2 p.Ser584= (c.1752G>A) is classified Likely benign in CUX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-04). Very rare (popmax 0.005%, amr); Associated with CUX2-related disorder.

What condition is associated with CUX2 p.Ser584= (c.1752G>A)?

CUX2 p.Ser584= (c.1752G>A) is associated with CUX2-related disorder (ClinVar).

How common is CUX2 p.Ser584= (c.1752G>A) in the general population?

CUX2 p.Ser584= (c.1752G>A) is very rare (popmax 0.005%, amr) (gnomAD).

CUX2 p.Ser584=

c.1752G>A · rs539297356 · VCV3044360

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 -14	GERP -3.6
Overall
CADD	0.989	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00116% 17/1,461,676 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,010
South Asian	0.0022%	45,544
African / African-American	0.00133%	75,070
European (non-Finnish)	0.000932%	107,274

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.Ser584=
Coding: c.1752G>A
MANE Select: NM_015267
dbSNP: rs539297356
Type: single nucleotide variant
Location: chr12:111310534 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 584: a DNA-binding 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-ser584 (accessed [today's date]).

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