Is CUX2 p.Ser479Phe (c.1436C>T) pathogenic?

CUX2 p.Ser479Phe (c.1436C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: ambiguous (0.39); Very rare (popmax 0.00226%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Ser479Phe (c.1436C>T)?

CUX2 p.Ser479Phe (c.1436C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Ser479Phe (c.1436C>T) in the general population?

CUX2 p.Ser479Phe (c.1436C>T) is very rare (popmax 0.00226%, amr) (gnomAD).

What do computational predictors say about CUX2 p.Ser479Phe (c.1436C>T)?

AlphaMissense predicts ambiguous (score 0.39) — an in-silico prediction, not a clinical call.

CUX2 p.Ser479Phe

c.1436C>T · rs746664186 · VCV2405861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.39 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.39	ambiguous
REVEL	0.285	benign-leaning
SaProt	LLR -6.56	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 318 bp · p 0.65 · regional, not allelic
Overall
CADD	26.8	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 0.00226% Admixed American · 1/44,204 alleles

Filtering AF 0.000304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.000727% 11/1,512,232 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00226%	44,204
Remaining individualsnot grpmax-eligible	0.00172%	57,980
South Asian	0.00134%	74,352
European (non-Finnish)	0.000708%	141,328

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.Ser479Phe
Coding: c.1436C>T
MANE Select: NM_015267
dbSNP: rs746664186
Type: single nucleotide variant
Location: chr12:111310218 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 479: 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-ser479phe (accessed [today's date]).

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