Is CUX1 p.Pro1057Ser (c.3169C>T) pathogenic?

CUX1 p.Pro1057Ser (c.3169C>T) is classified Uncertain significance in CUX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-31). AlphaMissense: likely pathogenic (0.6492); Absent from gnomAD v4.1.

How common is CUX1 p.Pro1057Ser (c.3169C>T) in the general population?

CUX1 p.Pro1057Ser (c.3169C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUX1 p.Pro1057Ser (c.3169C>T)?

AlphaMissense predicts likely pathogenic (score 0.6492) — an in-silico prediction, not a clinical call.

CUX1 p.Pro1057Ser

c.3169C>T · rs2485982652 · VCV2662603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6492 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6492	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 35 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	26.0	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

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: CUX1
Protein: p.Pro1057Ser
Coding: c.3169C>T
MANE Select: NM_181552
dbSNP: rs2485982652
Type: single nucleotide variant
Location: chr7:102227405 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.84 · 3 PDB
Residue 1057: the 'disordered' region; a UniProt-annotated variant site (in neddms)

Full CUX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUX1 p.Pro1057fs Likely pathogenic ★ same residue
CUX1 c.1451-2A>G Likely pathogenic ★★ same type
CUX1 c.1681-1G>A Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Arg661Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Gln862Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Glu866Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Trp1188Ter Pathogenic ★★ same type
CUX1 p.Ala1433Val Uncertain significance ★★ ⚠ same type

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-pro1057ser (accessed [today's date]).

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