Is CUX2 p.Pro988Ser (c.2962C>T) pathogenic?

CUX2 p.Pro988Ser (c.2962C>T) is classified Conflicting classifications of pathogenicity in CUX2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-16). AlphaMissense: likely benign (0.1365); Very rare (popmax 0.00333%, sas); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Pro988Ser (c.2962C>T)?

CUX2 p.Pro988Ser (c.2962C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Pro988Ser (c.2962C>T) in the general population?

CUX2 p.Pro988Ser (c.2962C>T) is very rare (popmax 0.00333%, sas) (gnomAD).

What do computational predictors say about CUX2 p.Pro988Ser (c.2962C>T)?

AlphaMissense predicts likely benign (score 0.1365) — an in-silico prediction, not a clinical call.

CUX2 p.Pro988Ser

c.2962C>T · rs1259294051 · VCV2643307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1365	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.74 · regional, not allelic
Overall
CADD	23.8	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 0.00333% South Asian · 3/90,186 alleles

Filtering AF 0.000884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000445%

Overall 0.000344% 5/1,451,678 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00333%	30,062
European (non-Finnish)	0.00017%	587,430

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.Pro988Ser
Coding: c.2962C>T
MANE Select: NM_015267
dbSNP: rs1259294051
Type: single nucleotide variant
Location: chr12:111334476 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 988: the 'disordered' region

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-pro988ser (accessed [today's date]).

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