Is CUX2 p.Ser1397= (c.4191G>A) pathogenic?

CUX2 p.Ser1397= (c.4191G>A) is classified Likely benign in CUX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-08). Ultra-rare (popmax 0.0312%, eas); Associated with CUX2-related disorder.

What condition is associated with CUX2 p.Ser1397= (c.4191G>A)?

CUX2 p.Ser1397= (c.4191G>A) is associated with CUX2-related disorder (ClinVar).

How common is CUX2 p.Ser1397= (c.4191G>A) in the general population?

CUX2 p.Ser1397= (c.4191G>A) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

CUX2 p.Ser1397=

c.4191G>A · rs745631840 · VCV3047090

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

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 -8.8	GERP -3.2
Overall
CADD	0.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,890 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00223% 36/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,206
Middle Eastern	0.0164%	6,084
South Asian	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	63,950
European (non-Finnish)	0.00136%	73,751

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.Ser1397=
Coding: c.4191G>A
MANE Select: NM_015267
dbSNP: rs745631840
Type: single nucleotide variant
Location: chr12:111348055 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 1397: 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.Ser1397Leu Uncertain significance ★ ⚠ same residue
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

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-ser1397 (accessed [today's date]).

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