Is CNTNAP2 p.Asp1237fs (c.3709del) pathogenic?

CNTNAP2 p.Asp1237fs (c.3709del) is classified Pathogenic in CNTNAP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-19). Very rare (popmax 0.00017%, nfe); Associated with cortical dysplasia-focal epilepsy syndrome.

What condition is associated with CNTNAP2 p.Asp1237fs (c.3709del)?

CNTNAP2 p.Asp1237fs (c.3709del) is associated with cortical dysplasia-focal epilepsy syndrome (ClinVar).

How common is CNTNAP2 p.Asp1237fs (c.3709del) in the general population?

CNTNAP2 p.Asp1237fs (c.3709del) is very rare (popmax 0.00017%, nfe) (gnomAD).

CNTNAP2 p.Asp1237fs

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.3709del · rs730880275 · VCV5490

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

cortical dysplasia-focal epilepsy syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7	phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,934 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00112% 18/1,613,566 alleles · very rare exomes 2/1,461,372 · genomes 16/152,194 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.75%	57
European (non-Finnish)grpmax	0.00017%	589,967

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp1237fs
Coding: c.3709del
MANE Select: NM_014141
dbSNP: rs730880275
Type: Deletion
Location: chr7:148383881 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.81 · 1 PDB

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.Asn454fs Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Gly1161fs Pathogenic ★★ same condition
CNTNAP2 p.Trp833fs Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 c.2773+76del Benign ★★ same condition
CNTNAP2 c.3797-14_3797-12del Likely benign ★★ same condition
CNTNAP2 c.551-8del Benign/Likely benign ★★ same condition
CNTNAP2 c.3345_3381+346del Likely pathogenic ★ same condition
CNTNAP2 p.Asn1198fs 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-asp1237fs (accessed [today's date]).

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