Is CUX2 p.Val27Phe (c.79G>T) pathogenic?

CUX2 p.Val27Phe (c.79G>T) is classified Conflicting classifications of pathogenicity in CUX2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-24). AlphaMissense: likely pathogenic (0.5819); Ultra-rare (popmax 0.0611%, nfe); Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Val27Phe (c.79G>T)?

CUX2 p.Val27Phe (c.79G>T) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Val27Phe (c.79G>T) in the general population?

CUX2 p.Val27Phe (c.79G>T) is ultra-rare (popmax 0.0611%, nfe) (gnomAD).

What do computational predictors say about CUX2 p.Val27Phe (c.79G>T)?

AlphaMissense predicts likely pathogenic (score 0.5819) — an in-silico prediction, not a clinical call.

CUX2 p.Val27Phe

c.79G>T · rs200420920 · VCV1175839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5819 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0611%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
AlphaMissense	0.5819	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 180 kb · p 0.91 · regional, not allelic
Overall
CADD	22.3	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

Grpmax group 0.0611% European (non-Finnish) · 686/1,122,712 alleles

Filtering AF 0.0573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0558%

Overall 0.0508% 761/1,496,796 alleles · ultra-rare exomes 697/1,360,546 · genomes 64/136,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0611%	1,637
South Asian	0.0463%	2,160
Remaining individualsnot grpmax-eligible	0.0348%	2,875
African / African-American	0.0203%	4,934
Admixed American	0.0136%	7,373
East Asian	0.00247%	40,540

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.Val27Phe
Coding: c.79G>T
MANE Select: NM_015267
dbSNP: rs200420920
Type: single nucleotide variant
Location: chr12:111214215 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB

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.Val27= Benign/Likely benign ★★ same residue
CUX2 p.Val27Ile Conflicting classifications of pathogenicity ★ ⚠ 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

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-val27phe (accessed [today's date]).

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