Is CUX2 p.Pro727Leu (c.2180C>T) pathogenic?

CUX2 p.Pro727Leu (c.2180C>T) is classified Uncertain significance in CUX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-15). AlphaMissense: likely benign (0.0774); Absent from gnomAD v4.1; Associated with CUX2-related disorder.

What condition is associated with CUX2 p.Pro727Leu (c.2180C>T)?

CUX2 p.Pro727Leu (c.2180C>T) is associated with CUX2-related disorder (ClinVar).

How common is CUX2 p.Pro727Leu (c.2180C>T) in the general population?

CUX2 p.Pro727Leu (c.2180C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUX2 p.Pro727Leu (c.2180C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

CUX2 p.Pro727Leu

c.2180C>T · rs1887444931 · VCV2632906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CUX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.81	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 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,582 bp · p 0.88 · regional, not allelic
Overall
CADD	21.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CUX2
Protein: p.Pro727Leu
Coding: c.2180C>T
MANE Select: NM_015267
dbSNP: rs1887444931
Type: single nucleotide variant
Location: chr12:111320189 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 727: the 'disordered' region

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

Disease context

CUX2-related disorder

Similar variants

CUX2 c.560+2T>C Uncertain significance ★ same condition
CUX2 p.Arg225Gln Uncertain significance ★ ⚠ same condition
CUX2 p.Pro1089Ser Likely pathogenic same condition
CUX2 p.Asp237Glu Uncertain significance ⚠ same condition
CUX2 p.Thr875Ala Uncertain significance ⚠ same condition
CUX2 c.63+9G>C Likely benign same condition
CUX2 c.637+10G>A Likely benign same condition
CUX2 c.705-3C>T Likely benign 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-pro727leu (accessed [today's date]).

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