Is CUX2 p.Pro1045Ser (c.3133C>T) pathogenic?

CUX2 p.Pro1045Ser (c.3133C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-19). AlphaMissense: likely benign (0.1176); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Pro1045Ser (c.3133C>T)?

CUX2 p.Pro1045Ser (c.3133C>T) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Pro1045Ser (c.3133C>T) in the general population?

CUX2 p.Pro1045Ser (c.3133C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUX2 p.Pro1045Ser (c.3133C>T)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

CUX2 p.Pro1045Ser

c.3133C>T · rs759732385 · VCV1098638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.74 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CUX2
Protein: p.Pro1045Ser
Coding: c.3133C>T
MANE Select: NM_015267
dbSNP: rs759732385
Type: single nucleotide variant
Location: chr12:111334647 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 1045: a DNA-binding region

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

Disease context

developmental and epileptic encephalopathy, 67 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUX2 p.Glu590Lys Pathogenic/Likely pathogenic ★★ same condition
CUX2 p.Ala336Thr Uncertain significance ★★ ⚠ same condition
CUX2 p.Ala544Val Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg599Ser Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg903His Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp844Gly Uncertain significance ★★ ⚠ same condition
CUX2 p.Ile429Met Uncertain significance ★★ ⚠ 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-pro1045ser (accessed [today's date]).

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