Is CUX2 p.Pro535Ser (c.1603C>T) pathogenic?

CUX2 p.Pro535Ser (c.1603C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: likely benign (0.075); Very rare (popmax 0.00267%, afr); Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Pro535Ser (c.1603C>T)?

CUX2 p.Pro535Ser (c.1603C>T) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Pro535Ser (c.1603C>T) in the general population?

CUX2 p.Pro535Ser (c.1603C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CUX2 p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

CUX2 p.Pro535Ser

c.1603C>T · rs1365473132 · VCV1696486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.101	moderately 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 0.32	GERP -3, phastCons 0.38
Regional constraint	o/e 1.04	unconstrained · MANE · 318 bp · p 0.65 · regional, not allelic
Overall
CADD	10.77	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

Grpmax group 0.00267% African / African-American · 2/74,790 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000125% 2/1,603,288 alleles · very rare exomes 1/1,451,018 · genomes 1/152,270 · joint denominator

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.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_015267
dbSNP: rs1365473132
Type: single nucleotide variant
Location: chr12:111310385 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 535: the 'disordered' region

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

Disease context

developmental and epileptic encephalopathy, 67 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUX2 p.Pro535= Likely benign ★★ same residue
CUX2 p.Glu590Lys Pathogenic/Likely pathogenic ★★ same condition
CUX2 p.Ala336Thr Uncertain significance ★★ ⚠ same condition
CUX2 p.Ala544Val Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg599Ser Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg903His Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp844Gly 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-pro535ser (accessed [today's date]).

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