Is CUX2 p.Pro985Thr (c.2953C>A) pathogenic?

CUX2 p.Pro985Thr (c.2953C>A) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: likely benign (0.2183); Very rare (popmax 0.00443%, sas); Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Pro985Thr (c.2953C>A)?

CUX2 p.Pro985Thr (c.2953C>A) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Pro985Thr (c.2953C>A) in the general population?

CUX2 p.Pro985Thr (c.2953C>A) is very rare (popmax 0.00443%, sas) (gnomAD).

What do computational predictors say about CUX2 p.Pro985Thr (c.2953C>A)?

AlphaMissense predicts likely benign (score 0.2183) — an in-silico prediction, not a clinical call.

CUX2 p.Pro985Thr

c.2953C>A · rs1485751875 · VCV2572175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00443%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
AlphaMissense	0.2183	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.74 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.00443% South Asian · 4/90,360 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000897%

Overall 0.000344% 5/1,454,722 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00443%	22,590
Remaining individualsnot grpmax-eligible	0.00161%	62,114

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.Pro985Thr
Coding: c.2953C>A
MANE Select: NM_015267
dbSNP: rs1485751875
Type: single nucleotide variant
Location: chr12:111334467 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 985: the 'disordered' 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-pro985thr (accessed [today's date]).

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