Is CUX2 p.Val27= (c.81C>T) pathogenic?

CUX2 p.Val27= (c.81C>T) is classified Benign/Likely benign in CUX2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). Rare (popmax 0.353%, nfe); Associated with developmental and epileptic encephalopathy, 67.

What condition is associated with CUX2 p.Val27= (c.81C>T)?

CUX2 p.Val27= (c.81C>T) is associated with developmental and epileptic encephalopathy, 67 (ClinVar).

How common is CUX2 p.Val27= (c.81C>T) in the general population?

CUX2 p.Val27= (c.81C>T) is rare (popmax 0.353%, nfe) (gnomAD).

CUX2 p.Val27=

c.81C>T · rs190091435 · VCV713817

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.353%, nfe)

Conditions

developmental and epileptic encephalopathy, 67

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.015	GERP -1.1, phastCons 0.83
Overall
CADD	8.627	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.353% European (non-Finnish) · 4,049/1,146,786 alleles

Filtering AF 0.344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.34%

Overall 0.295% 4,545/1,540,248 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.353%	283
Finnishnot grpmax-eligible	0.29%	345
Remaining individualsnot grpmax-eligible	0.288%	347
Admixed American	0.115%	867
Ashkenazi Jewishnot grpmax-eligible	0.0943%	1,060
African / African-American	0.0725%	1,379
South Asian	0.0176%	5,694
Middle Eastern	0.0173%	5,776
East Asian	0.00237%	42,160

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.Val27=
Coding: c.81C>T
MANE Select: NM_015267
dbSNP: rs190091435
Type: single nucleotide variant
Location: chr12:111214217 (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.Val27Phe Conflicting classifications of pathogenicity ★ ⚠ 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-val27 (accessed [today's date]).

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