# NM_003632.3(CNTNAP1):c.3612A>G (p.Pro1204=)

https://sugi.bio/variant/cntnap1-p-pro1204

## Summary

**CNTNAP1 p.Pro1204= (c.3612A>G)** is classified **Likely benign** in CNTNAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). Ultra-rare (popmax 0.01%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs756999207 · 1 submitter · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the CNTNAP1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNTNAP1](https://sugi.bio/atlas/gene/CNTNAP1/) |
| Protein change (HGVS p.) | p.Pro1204= |
| Coding change (HGVS c.) | c.3612A>G |
| MANE Select transcript | [NM_003632](https://www.ncbi.nlm.nih.gov/nuccore/NM_003632) |
| dbSNP | [rs756999207](https://www.ncbi.nlm.nih.gov/snp/rs756999207/) |
| Variant type | single nucleotide variant |
| Location | chr17:42697597-42697597 (GRCh38) |
| ClinVar | [VCV1622887](https://www.ncbi.nlm.nih.gov/clinvar/variation/1622887/) |

**All HGVS expressions:** `NC_000017.10:g.40849615A>G`, `NC_000017.11:g.42697597A>G`, `NG_042091.1:g.19984A>G`, `NM_003632.3:c.3612A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.895, GERP -5.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.83**. 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 deltas (raw): acceptor loss **0.04**, donor loss **0.03**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.01%** (amr) · FAF95 0.00428% · FAF99 0.00295% · 6/59,986 in the highest group · 10/1,613,928 alleles overall — ultra-rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 9,998 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |
| European (non-Finnish) | 0.000169% | 590,009 |

*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}

**CNTNAP1** population constraint: LOEUF 0.578, pLI 1.514e-07, missense-Z 3.8452. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **1204** lies in the laminin g-like 4 domain; a UniProt-annotated variant site (in chn3); a UniProt-annotated variant site (in lccs7 and chn3); a UniProt-annotated variant site (in lccs7).

AlphaFold model confidence (whole protein): pLDDT 81.51, 50% of residues very-high.

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

*Describes the biological roles of CNTNAP1 (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.*


### Pathways affected {#pathways}

CNTNAP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurofascin interactions](https://reactome.org/content/detail/R-HSA-447043) | electronic |

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

**Biological process:** central nervous system myelination, myelination in peripheral nervous system, paranodal junction assembly, neuron projection morphogenesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CNTNAP1 variant pages (same residue, condition, or type): [CNTNAP1 p.Arg1121Ter](/variant/cntnap1-p-arg1121ter), [CNTNAP1 p.Arg618Ter](/variant/cntnap1-p-arg618ter), [CNTNAP1 p.Arg697Ter](/variant/cntnap1-p-arg697ter), [CNTNAP1 p.Arg835Ter](/variant/cntnap1-p-arg835ter), [CNTNAP1 p.Arg890Ter](/variant/cntnap1-p-arg890ter), [CNTNAP1 p.Trp672Ter](/variant/cntnap1-p-trp672ter), [CNTNAP1 c.3568+10G>A](/variant/cntnap1-c-3568-plus-10g-a), [CNTNAP1 p.Ala1322Thr](/variant/cntnap1-p-ala1322thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1622887). 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.*