# NM_000743.5(CHRNA3):c.200C>T (p.Ser67Phe)

https://sugi.bio/variant/chrna3-p-ser67phe

## Summary

**CHRNA3 p.Ser67Phe (c.200C>T)** is classified **Uncertain significance** in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-29). AlphaMissense: likely pathogenic (0.5659); Very rare (popmax 0.00167%, amr); Associated with SMOKING AS A QUANTITATIVE TRAIT LOCUS 3.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CHRNA3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to SMOKING AS A QUANTITATIVE TRAIT LOCUS 3.

*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 | [CHRNA3](https://sugi.bio/atlas/gene/CHRNA3/) |
| Protein change (HGVS p.) | p.Ser67Phe |
| Coding change (HGVS c.) | c.200C>T |
| MANE Select transcript | [NM_000743](https://www.ncbi.nlm.nih.gov/nuccore/NM_000743) |
| Variant type | single nucleotide variant |
| Location | chr15:78618798-78618798 (GRCh38) |
| ClinVar | [VCV3577774](https://www.ncbi.nlm.nih.gov/clinvar/variation/3577774/) |

**All HGVS expressions:** `NC_000015.10:g.78618798G>A`, `NC_000015.9:g.78911140G>A`, `NG_016143.1:g.7498C>T`, `NM_000743.5:c.200C>T`, `NM_001166694.2:c.200C>T`, `NR_046313.2:n.402C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5659)
- REVEL 0.693 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.441 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.674, GERP 1.93, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.4**. 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 0.85** across the covering region of the MANE Select transcript (78,596,607–78,620,794), spanning 24,187 bp. Chi-square p 0.00014. 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>C, Δ0.49 donor 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 **0.00167%** (amr) · 1/60,032 in the highest group · 1/1,461,778 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**CHRNA3** population constraint: LOEUF 1.065, pLI 2.7242e-10, missense-Z 1.6569. *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 **67** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 81.97, 62% of residues very-high.

**5 experimental structure(s)** (PDB): [4ZK4](https://www.rcsb.org/structure/4ZK4), [5SYO](https://www.rcsb.org/structure/5SYO), [5TVC](https://www.rcsb.org/structure/5TVC), [6PV7](https://www.rcsb.org/structure/6PV7), [6PV8](https://www.rcsb.org/structure/6PV8).

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

*Describes the biological roles of CHRNA3 (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:** CHRNA3's established molecular role includes acetylcholine receptor activity.


### Pathways affected {#pathways}

CHRNA3 participates in **3 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 |
| [Highly sodium permeable postsynaptic acetylcholine nicotinic receptors](https://reactome.org/content/detail/R-HSA-629587) | curated |

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

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

**Biological process:** signal transduction, nervous system development, regulation of appetite, behavioral response to nicotine, synaptic transmission involved in micturition, acetylcholine receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-29 |

## Associated conditions {#conditions}

[SMOKING AS A QUANTITATIVE TRAIT LOCUS 3](https://sugi.bio/atlas/disease/smoking-as-a-quantitative-trait-locus-3/), [urinary bladder, atony of](https://sugi.bio/atlas/disease/urinary-bladder-atony-of/).

**Reported phenotype names (ClinVar):** SMOKING AS A QUANTITATIVE TRAIT LOCUS 3, Urinary bladder, atony of, Bladder Dysfunction with Impaired Pupillary Reflex and Secondary Congenital Anomalies of the Kidney and Urinary Tract.

## Similar variants {#similar}

Related CHRNA3 variant pages (same residue, condition, or type): [CHRNA3 p.Trp180Ter](/variant/chrna3-p-trp180ter), [CHRNA3 p.Arg477His](/variant/chrna3-p-arg477his), [CHRNA3 p.Asn92Ser](/variant/chrna3-p-asn92ser), [CHRNA3 p.Asp230Asn](/variant/chrna3-p-asp230asn), [CHRNA3 p.Gly390Ala](/variant/chrna3-p-gly390ala), [CHRNA3 p.Gly493Ala](/variant/chrna3-p-gly493ala), [CHRNA3 p.Leu380Val](/variant/chrna3-p-leu380val), [CHRNA3 p.Pro498Leu](/variant/chrna3-p-pro498leu).

### 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 3577774). 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.*