Is CUX2 p.Pro608Ser (c.1822C>T) pathogenic?

CUX2 p.Pro608Ser (c.1822C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.9637); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Pro608Ser (c.1822C>T)?

CUX2 p.Pro608Ser (c.1822C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Pro608Ser (c.1822C>T) in the general population?

CUX2 p.Pro608Ser (c.1822C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUX2 p.Pro608Ser (c.1822C>T)?

AlphaMissense predicts likely pathogenic (score 0.9637) — an in-silico prediction, not a clinical call.

CUX2 p.Pro608Ser

c.1822C>T · VCV4008424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9637 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9637	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -5.21	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 1,727 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	29.3	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: CUX2
Protein: p.Pro608Ser
Coding: c.1822C>T
MANE Select: NM_015267
Type: single nucleotide variant
Location: chr12:111310604 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 608: 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.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-pro608ser (accessed [today's date]).

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