Is CUX2 p.Pro493Thr (c.1477C>A) pathogenic?

CUX2 p.Pro493Thr (c.1477C>A) is classified Likely benign in CUX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.0681); Ultra-rare (popmax 0.0182%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Pro493Thr (c.1477C>A)?

CUX2 p.Pro493Thr (c.1477C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Pro493Thr (c.1477C>A) in the general population?

CUX2 p.Pro493Thr (c.1477C>A) is ultra-rare (popmax 0.0182%, amr) (gnomAD).

What do computational predictors say about CUX2 p.Pro493Thr (c.1477C>A)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

CUX2 p.Pro493Thr

c.1477C>A · rs202129111 · VCV2454222

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -7.36	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 1.9	GERP -1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 318 bp · p 0.65 · regional, not allelic
Overall
CADD	17.17	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 0.0182% Admixed American · 8/44,014 alleles

Filtering AF 0.00898% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.00571% 86/1,506,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0182%	5,502
Middle Eastern	0.018%	5,560
European (non-Finnish)	0.00674%	14,830
Remaining individualsnot grpmax-eligible	0.00173%	57,722

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.Pro493Thr
Coding: c.1477C>A
MANE Select: NM_015267
dbSNP: rs202129111
Type: single nucleotide variant
Location: chr12:111310259 (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-pro493thr (accessed [today's date]).

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