# NM_000742.4(CHRNA2):c.131C>G (p.Pro44Arg)

https://sugi.bio/variant/chrna2-p-pro44arg

## Summary

**CHRNA2 p.Pro44Arg (c.131C>G)** is classified **Uncertain significance** in CHRNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-24). AlphaMissense: likely benign (0.0627); Very rare (popmax 6.84e-05%); Associated with familial sleep-related hypermotor epilepsy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs778838030 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 6.84e-05%)

## For patients & families {#patients}

This is a change in the CHRNA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to familial sleep-related hypermotor epilepsy.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | CHRNA2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Sleep-related hypermotor epilepsy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Nocturnal seizures — Very frequent (99-80%)
- Abnormal repetitive mannerisms — Frequent (79-30%)
- Paroxysmal dystonia — Frequent (79-30%)
- Involuntary movements — Frequent (79-30%)
- Urinary incontinence — Occasional (29-5%)
- Depression — Occasional (29-5%)
- Anxiety — Occasional (29-5%)
- Hyperventilation — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022703/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHRNA2](https://sugi.bio/atlas/gene/CHRNA2/) |
| Protein change (HGVS p.) | p.Pro44Arg |
| Coding change (HGVS c.) | c.131C>G |
| MANE Select transcript | [NM_000742](https://www.ncbi.nlm.nih.gov/nuccore/NM_000742) |
| dbSNP | [rs778838030](https://www.ncbi.nlm.nih.gov/snp/rs778838030/) |
| Variant type | single nucleotide variant |
| Location | chr8:27469924-27469924 (GRCh38) |
| ClinVar | [VCV2795538](https://www.ncbi.nlm.nih.gov/clinvar/variation/2795538/) |

**All HGVS expressions:** `NC_000008.10:g.27327441G>C`, `NC_000008.11:g.27469924G>C`, `NG_015827.1:g.14373C>G`, `NM_000742.4:c.131C>G`, `NM_001282455.2:c.131C>G`, `NM_001347705.2:c.-297C>G`, `NM_001347706.2:c.-342C>G`, `NM_001347707.2:c.-283C>G`, `NM_001347708.2:c.-331C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0627)
- REVEL 0.021 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.532 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.032, GERP 1.07 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.06**. 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.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (27,463,654–27,471,058), spanning 7,404 bp. Chi-square p 0.095. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.51 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): global (via dbSNP) **6.84e-05%** · 1/1,461,810 alleles overall — very rare (popmax 6.84e-05%).

*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}

**CHRNA2** population constraint: LOEUF 1.195, pLI 1.7932e-12, missense-Z 0.89981. *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):

- **familial sleep-related hypermotor epilepsy** — Limited (AD)
- **benign familial infantile epilepsy** — Disputed (AD)

## Protein context {#protein}

Residue **44** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.88, 50% of residues very-high.

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

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

*Describes the biological roles of CHRNA2 (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:** CHRNA2's established molecular role includes acetylcholine receptor activity. p.Pro44Arg falls in the disordered region.


### Pathways affected {#pathways}

CHRNA2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Highly calcium permeable nicotinic acetylcholine receptors](https://reactome.org/content/detail/R-HSA-629597) | curated |
| [Highly calcium permeable postsynaptic nicotinic acetylcholine receptors](https://reactome.org/content/detail/R-HSA-629594) | curated |

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

**Molecular function:** acetylcholine receptor activity, acetylcholine-gated monoatomic cation-selective channel activity.

**Biological process:** signal transduction, acetylcholine receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-24 |

## Associated conditions {#conditions}

[familial sleep-related hypermotor epilepsy](https://sugi.bio/atlas/disease/familial-sleep-related-hypermotor-epilepsy/).

**Reported phenotype names (ClinVar):** Familial sleep-related hypermotor epilepsy, Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.

## Similar variants {#similar}

Related CHRNA2 variant pages (same residue, condition, or type): [CHRNA2 p.Pro44=](/variant/chrna2-p-pro44), [CHRNA2 p.Pro44Leu](/variant/chrna2-p-pro44leu), [CHRNA2 c.1464+4C>T](/variant/chrna2-c-1464-plus-4c-t), [CHRNA2 c.1464+5G>A](/variant/chrna2-c-1464-plus-5g-a), [CHRNA2 c.294+1G>A](/variant/chrna2-c-294-plus-1g-a), [CHRNA2 c.294+5G>A](/variant/chrna2-c-294-plus-5g-a), [CHRNA2 c.449+3A>T](/variant/chrna2-c-449-plus-3a-t), [CHRNA2 c.73+4A>C](/variant/chrna2-c-73-plus-4a-c).

### 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 2795538). 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.*