Is CUX2 p.Ser1416Phe (c.4247C>T) pathogenic?

CUX2 p.Ser1416Phe (c.4247C>T) is classified Uncertain significance in CUX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.328); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Ser1416Phe (c.4247C>T)?

CUX2 p.Ser1416Phe (c.4247C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Ser1416Phe (c.4247C>T) in the general population?

CUX2 p.Ser1416Phe (c.4247C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CUX2 p.Ser1416Phe (c.4247C>T)?

AlphaMissense predicts likely benign (score 0.328) — an in-silico prediction, not a clinical call.

CUX2 p.Ser1416Phe

c.4247C>T · VCV4236231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.328	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -8.53	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 771 bp · p 0.075 · regional, not allelic
Overall
CADD	26.8	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 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00041% 6/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,345

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.Ser1416Phe
Coding: c.4247C>T
MANE Select: NM_015267
Type: single nucleotide variant
Location: chr12:111348111 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 1416: 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-ser1416phe (accessed [today's date]).

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