Is CUX2 p.Gln561Arg (c.1682A>G) pathogenic?

CUX2 p.Gln561Arg (c.1682A>G) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). AlphaMissense: ambiguous (0.4042); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Gln561Arg (c.1682A>G)?

CUX2 p.Gln561Arg (c.1682A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Gln561Arg (c.1682A>G) in the general population?

CUX2 p.Gln561Arg (c.1682A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CUX2 p.Gln561Arg (c.1682A>G)?

AlphaMissense predicts ambiguous (score 0.4042) — an in-silico prediction, not a clinical call.

CUX2 p.Gln561Arg

c.1682A>G · VCV4236249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4042	ambiguous
REVEL	0.452	indeterminate
SaProt	LLR -4.88	tolerated
Splicing
SpliceAI	Δ0.23	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 1,727 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	27.6	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 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,524 alleles · very rare

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.Gln561Arg
Coding: c.1682A>G
MANE Select: NM_015267
Type: single nucleotide variant
Location: chr12:111310464 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 561: a DNA-binding region; an α-helix

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.Gln561His Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-gln561arg (accessed [today's date]).

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