Is CUX1 p.Pro1253Ser (c.3757C>T) pathogenic?

CUX1 p.Pro1253Ser (c.3757C>T) is classified Uncertain significance in CUX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely pathogenic (0.9208); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CUX1 p.Pro1253Ser (c.3757C>T)?

CUX1 p.Pro1253Ser (c.3757C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX1 p.Pro1253Ser (c.3757C>T) in the general population?

CUX1 p.Pro1253Ser (c.3757C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CUX1 p.Pro1253Ser (c.3757C>T)?

AlphaMissense predicts likely pathogenic (score 0.9208) — an in-silico prediction, not a clinical call.

CUX1 p.Pro1253Ser

c.3757C>T · VCV3837503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9208	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 35 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	25.1	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 0.000169% European (non-Finnish) · 2/1,179,946 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,698 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: CUX1
Protein: p.Pro1253Ser
Coding: c.3757C>T
MANE Select: NM_181552
Type: single nucleotide variant
Location: chr7:102239454 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.84 · 3 PDB
Residue 1253: a DNA-binding region; a UniProt-annotated variant site (in neddms)

Full CUX1 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

CUX1 p.Pro1253Leu Uncertain significance ★ ⚠ same residue
CUX1 p.Ala1433Val Uncertain significance ★★ ⚠ same condition
CUX1 p.Asp1419Gly Uncertain significance ★★ ⚠ same condition
CUX1 p.Asp704Glu Uncertain significance ★★ ⚠ same condition
CUX1 p.Cys802Tyr Uncertain significance ★★ ⚠ same condition
CUX1 p.Gly543Arg Uncertain significance ★★ ⚠ same condition
CUX1 p.His1293Tyr Uncertain significance ★★ ⚠ same condition
CUX1 p.Ile160Thr 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/cux1-p-pro1253ser (accessed [today's date]).

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