Is CUX2 p.Arg128Trp (c.382C>T) pathogenic?

CUX2 p.Arg128Trp (c.382C>T) is classified Likely benign in CUX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely benign (0.0865); Very rare (popmax 0.00331%, sas); Associated with intellectual disability.

What condition is associated with CUX2 p.Arg128Trp (c.382C>T)?

CUX2 p.Arg128Trp (c.382C>T) is associated with intellectual disability (ClinVar).

How common is CUX2 p.Arg128Trp (c.382C>T) in the general population?

CUX2 p.Arg128Trp (c.382C>T) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about CUX2 p.Arg128Trp (c.382C>T)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

CUX2 p.Arg128Trp

c.382C>T · rs749551874 · VCV975535

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.98	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 3.2	GERP 1.3, phastCons 0.96
Regional constraint	o/e 0.74	unconstrained · MANE · 93 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% South Asian · 3/90,568 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.00062% 10/1,612,456 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,189
African / African-American	0.00267%	37,460
Admixed American	0.00167%	59,800
European (non-Finnish)	0.000339%	294,819

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.Arg128Trp
Coding: c.382C>T
MANE Select: NM_015267
dbSNP: rs749551874
Type: single nucleotide variant
Location: chr12:111291498 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 128: the 'disordered' region

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUX2 p.Arg128Gln Likely benign ★ same residue
CUX2 p.Ala108Val Likely benign ★★ ⚠ same condition
CUX2 p.Gly1242Arg Likely benign ★★ same condition
CUX2 p.Thr405Lys Likely benign ★★ same condition
CUX2 p.Gly920Arg Uncertain significance ★ ⚠ same condition
CUX2 p.Ser806Leu Likely benign ⚠ same condition
CUX2 p.Glu590Lys Pathogenic/Likely pathogenic ★★ same type
CUX2 p.Ala302Ser Uncertain significance ★★ ⚠ same type

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-arg128trp (accessed [today's date]).

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