Is CUX2 p.Thr343= (c.1029G>A) pathogenic?

CUX2 p.Thr343= (c.1029G>A) is classified Benign/Likely benign in CUX2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-01). Rare (popmax 0.368%, nfe); Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Thr343= (c.1029G>A)?

CUX2 p.Thr343= (c.1029G>A) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Thr343= (c.1029G>A) in the general population?

CUX2 p.Thr343= (c.1029G>A) is rare (popmax 0.368%, nfe) (gnomAD).

CUX2 p.Thr343=

c.1029G>A · rs199929446 · VCV783039

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.368%, nfe)

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Constraint at this position
Conservation	phyloP -9.8	GERP -3.7
Overall
CADD	5.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.368% European (non-Finnish) · 4,343/1,179,068 alleles

Filtering AF 0.359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.355%

Overall 0.299% 4,817/1,612,796 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.568%	176
European (non-Finnish)grpmax	0.368%	271
Remaining individualsnot grpmax-eligible	0.259%	385
Admixed American	0.0984%	1,016
African / African-American	0.0626%	1,596
Finnishnot grpmax-eligible	0.0391%	2,557
Middle Eastern	0.033%	3,027
South Asian	0.00879%	11,378
East Asian	0.00669%	14,948

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr343=
Coding: c.1029G>A
MANE Select: NM_015267
dbSNP: rs199929446
Type: single nucleotide variant
Location: chr12:111307091 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB

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.Thr343Met Likely benign ★★ same residue
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

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-thr343 (accessed [today's date]).

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