# NM_014141.6(CNTNAP2):c.3709del (p.Asp1237fs)

https://sugi.bio/variant/cntnap2-p-asp1237fs

## Summary

**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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs730880275 · 4 submitters · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the CNTNAP2 gene that is considered disease-causing, submitted by 4 submitters, and is linked to cortical dysplasia-focal epilepsy syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | CNTNAP2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of CNTNAP2-related developmental and epileptic encephalopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Delayed speech and language development — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Abnormality of neuronal migration — Very frequent (99-80%)
- Focal-onset seizure — Very frequent (99-80%)
- Abnormal neuron morphology — Very frequent (99-80%)
- Delayed ability to walk — Very frequent (99-80%)
- Global developmental delay — Frequent (79-30%)
- Mental deterioration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016997/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNTNAP2](https://sugi.bio/atlas/gene/CNTNAP2/) |
| Protein change (HGVS p.) | p.Asp1237fs |
| Coding change (HGVS c.) | c.3709del |
| MANE Select transcript | [NM_014141](https://www.ncbi.nlm.nih.gov/nuccore/NM_014141) |
| dbSNP | [rs730880275](https://www.ncbi.nlm.nih.gov/snp/rs730880275/) |
| Variant type | Deletion |
| Location | chr7:148383881-148383881 (GRCh38) |
| ClinVar | [VCV5490](https://www.ncbi.nlm.nih.gov/clinvar/variation/5490/) |

**All HGVS expressions:** `NC_000007.13:g.148080974del`, `NC_000007.14:g.148383882del`, `NG_007092.3:g.2272882del`, `NM_014141.5:c.3709del`, `NM_014141.6:c.3709del`, `NM_014141.6:c.3709delG`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.023, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.721, pLI 1.9949e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 22 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,934 in the highest group · 18/1,613,566 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.75% | 57 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,967 |

Amish shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CNTNAP2** population constraint: LOEUF 0.721, pLI 1.9949e-18, missense-Z 0.26666; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Definitive (AR)
- **complex neurodevelopmental disorder** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.81, 58% of residues very-high.

**1 experimental structure(s)** (PDB): [5Y4M](https://www.rcsb.org/structure/5Y4M).

## What this gene does {#gene-function}

*Describes the biological roles of CNTNAP2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CNTNAP2's established molecular role includes enzyme binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme binding.

**Biological process:** learning, cell population proliferation, striatum development, limbic system development, thalamus development, cerebral cortex development.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-19.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2006–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2006-03-30 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-07 |

## Associated conditions {#conditions}

[cortical dysplasia-focal epilepsy syndrome](https://sugi.bio/atlas/disease/cortical-dysplasia-focal-epilepsy-syndrome/).

**Reported phenotype names (ClinVar):** Cortical dysplasia-focal epilepsy syndrome, not provided, none provided, Pitt-Hopkins-like syndrome 1.

## Similar variants {#similar}

Related CNTNAP2 variant pages (same residue, condition, or type): [CNTNAP2 p.Asn454fs](/variant/cntnap2-p-asn454fs), [CNTNAP2 p.Gly1161fs](/variant/cntnap2-p-gly1161fs), [CNTNAP2 p.Trp833fs](/variant/cntnap2-p-trp833fs), [CNTNAP2 c.2773+76del](/variant/cntnap2-c-2773-plus-76del), [CNTNAP2 c.3797-14_3797-12del](/variant/cntnap2-c-3797-minus-14-3797-minus-12del), [CNTNAP2 c.551-8del](/variant/cntnap2-c-551-minus-8del), [CNTNAP2 c.3345_3381+346del](/variant/cntnap2-c-3345-3381-plus-346del), [CNTNAP2 p.Asn1198fs](/variant/cntnap2-p-asn1198fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 5490). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*