Is CNTNAP2 p.Ala1026Val (c.3077C>T) pathogenic?

CNTNAP2 p.Ala1026Val (c.3077C>T) is classified Uncertain significance in CNTNAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.074); Very rare (popmax 8.47e-05%, nfe); Associated with cortical dysplasia-focal epilepsy syndrome.

What condition is associated with CNTNAP2 p.Ala1026Val (c.3077C>T)?

CNTNAP2 p.Ala1026Val (c.3077C>T) is associated with cortical dysplasia-focal epilepsy syndrome (ClinVar).

How common is CNTNAP2 p.Ala1026Val (c.3077C>T) in the general population?

CNTNAP2 p.Ala1026Val (c.3077C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CNTNAP2 p.Ala1026Val (c.3077C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

CNTNAP2 p.Ala1026Val

Q: How is CNTNAP2-related developmental and epileptic encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.3077C>T · rs2536642047 · VCV2792610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cortical dysplasia-focal epilepsy syndrome

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.53	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 1.5	GERP 1.7, phastCons 0.45
Regional constraint	o/e 1.02	unconstrained · MANE · 2,299 kb · p 0.34 · regional, not allelic
Overall
CADD	7.13	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,052 alleles · very rare exomes 1/1,461,888 · genomes 0/152,164 · joint denominator

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: CNTNAP2
Protein: p.Ala1026Val
Coding: c.3077C>T
MANE Select: NM_014141
dbSNP: rs2536642047
Type: single nucleotide variant
Location: chr7:148217354 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.81 · 1 PDB
Residue 1026: the 'disordered' region

Full CNTNAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cortical dysplasia-focal epilepsy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CNTNAP2-related developmental and epileptic encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CNTNAP2 p.Ala1026Thr Uncertain significance ★★ ⚠ same residue
CNTNAP2 c.1348+1G>A Likely pathogenic ★★ same condition
CNTNAP2 c.3382-2A>C Likely pathogenic ★★ same condition
CNTNAP2 c.97+1G>A Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg1088Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg1095Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg483Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Gln1111Ter Pathogenic/Likely pathogenic ★★ 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/cntnap2-p-ala1026val (accessed [today's date]).

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