Is CUX2 p.Arg258Trp (c.772C>T) pathogenic?

CUX2 p.Arg258Trp (c.772C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: ambiguous (0.5564); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Arg258Trp (c.772C>T)?

CUX2 p.Arg258Trp (c.772C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Arg258Trp (c.772C>T) in the general population?

CUX2 p.Arg258Trp (c.772C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CUX2 p.Arg258Trp (c.772C>T)?

AlphaMissense predicts ambiguous (score 0.5564) — an in-silico prediction, not a clinical call.

CUX2 p.Arg258Trp

c.772C>T · VCV4008421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5564	ambiguous
REVEL	0.339	indeterminate
SaProt	LLR -10.93	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 93 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	29.4	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 0.00167% Admixed American · 1/59,936 alleles

Overall 0.000137% 2/1,461,212 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,936
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Arg258Trp
Coding: c.772C>T
MANE Select: NM_015267
Type: single nucleotide variant
Location: chr12:111304228 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUX2 p.Ala302Ser Uncertain significance ★★ ⚠ same condition
CUX2 p.Ala336Thr Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg701His Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg954Cys Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp1334Asn Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp844Gly Uncertain significance ★★ ⚠ same condition
CUX2 p.Pro423Ala 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-arg258trp (accessed [today's date]).

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