# NM_005076.5(CNTN2):c.105C>T (p.Phe35=)

https://sugi.bio/variant/cntn2-p-phe35

## Summary

**CNTN2 p.Phe35= (c.105C>T)** is classified **Benign/Likely benign** in CNTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Rare (popmax 0.246%, nfe); Associated with epilepsy, familial adult myoclonic, 5.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs147074435 · 3 submitters · 1 linked condition · rare (popmax 0.246%, nfe)

## For patients & families {#patients}

This is a change in the CNTN2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to epilepsy, familial adult myoclonic, 5.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018086/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNTN2](https://sugi.bio/atlas/gene/CNTN2/) |
| Protein change (HGVS p.) | p.Phe35= |
| Coding change (HGVS c.) | c.105C>T |
| MANE Select transcript | [NM_005076](https://www.ncbi.nlm.nih.gov/nuccore/NM_005076) |
| dbSNP | [rs147074435](https://www.ncbi.nlm.nih.gov/snp/rs147074435/) |
| Variant type | single nucleotide variant |
| Location | chr1:205057955-205057955 (GRCh38) |
| ClinVar | [VCV474457](https://www.ncbi.nlm.nih.gov/clinvar/variation/474457/) |

**All HGVS expressions:** `NC_000001.10:g.205027083C>T`, `NC_000001.11:g.205057955C>T`, `NG_033845.1:g.19744C>T`, `NM_001346083.2:c.105C>T`, `NM_005076.4:c.105C>T`, `NM_005076.5:c.105C>T`, `NR_144350.2:n.374C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.744, GERP -4.37 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.164**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.46 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.246%** (nfe) · FAF95 0.238% · FAF99 0.235% · 2,900/1,180,030 in the highest group · 3,429/1,614,148 alleles overall — rare (popmax 0.246%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.669% | 149 |
| Finnish (not grpmax-eligible) | 0.253% | 395 |
| European (non-Finnish) (grpmax) | 0.246% | 407 |
| Remaining individuals (not grpmax-eligible) | 0.173% | 579 |
| Admixed American | 0.055% | 1,819 |
| African / African-American | 0.0306% | 3,264 |
| Middle Eastern | 0.0165% | 6,046 |
| South Asian | 0.00439% | 22,770 |

Ashkenazi Jewish 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}

**CNTN2** population constraint: LOEUF 0.542, pLI 0.019495, missense-Z 3.3008. *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)

## Protein context {#protein}

Residue **35** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 86.13, 58% of residues very-high.

**5 experimental structure(s)** (PDB): [2OM5](https://www.rcsb.org/structure/2OM5), [8K3J](https://www.rcsb.org/structure/8K3J), [8K53](https://www.rcsb.org/structure/8K53), [9BA4](https://www.rcsb.org/structure/9BA4), [9BA5](https://www.rcsb.org/structure/9BA5).

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

*Describes the biological roles of CNTN2 (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}

CNTN2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [L1CAM interactions](https://reactome.org/content/detail/R-HSA-373760) | electronic |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |
| [NrCAM interactions](https://reactome.org/content/detail/R-HSA-447038) | electronic |

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

**Biological process:** presynaptic membrane organization.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-04-22 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-20 |

## Associated conditions {#conditions}

[epilepsy, familial adult myoclonic, 5](https://sugi.bio/atlas/disease/epilepsy-familial-adult-myoclonic-5/).

**Reported phenotype names (ClinVar):** Epilepsy, familial adult myoclonic, 5, CNTN2-related disorder, not specified, CNTN2-related condition, AllHighlyPenetrant, CORTICAL MYOCLONIC TREMOR WITH EPILEPSY, FAMILIAL, 5.

## Similar variants {#similar}

Related CNTN2 variant pages (same residue, condition, or type): [CNTN2 c.1241-1G>C](/variant/cntn2-c-1241-minus-1g-c), [CNTN2 c.2432-2A>G](/variant/cntn2-c-2432-minus-2a-g), [CNTN2 p.Arg140Ter](/variant/cntn2-p-arg140ter), [CNTN2 p.Arg314Ter](/variant/cntn2-p-arg314ter), [CNTN2 p.Trp731Ter](/variant/cntn2-p-trp731ter), [CNTN2 c.2196+5G>A](/variant/cntn2-c-2196-plus-5g-a), [CNTN2 p.Ala230Val](/variant/cntn2-p-ala230val), [CNTN2 p.Ala263Thr](/variant/cntn2-p-ala263thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 474457). 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.*