CHRNA1

Chr 2ARAD

cholinergic receptor nicotinic alpha 1 subunit

Also known as: ACHRA, ACHRD, CHRNA, CMS1A, CMS1B, CMS2A, FCCMS, SCCMS

NCBI Gene: 1134 ENSG00000138435 UniProt: P02708 OMIM: 100690

The protein encodes the alpha subunit of the muscle acetylcholine receptor, which binds acetylcholine and gates the ion channel at the neuromuscular junction. Mutations cause congenital myasthenic syndromes (both slow-channel and fast-channel types) and lethal multiple pterygium syndrome through gain-of-function mechanisms. Inheritance is autosomal recessive for most phenotypes, though autosomal dominant transmission occurs in slow-channel myasthenic syndrome.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 1.083 OMIM phenotypes

Clinical Summary— CHRNA1

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Gene-Disease Validity (ClinGen)

myasthenic syndrome, congenital, 1B, fast-channel · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

52 unique Pathogenic / Likely Pathogenic· 276 VUS of 591 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHRNA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.08LOEUF

pLI 0.000

Z-score 1.28

OE 0.70 (0.47–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.72Z-score

OE missense 0.88 (0.79–0.98)

250 obs / 284.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.47–1.08)

0≤0.351.4

Missense OE?0.88 (0.79–0.98)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 21.4Missense obs/exp: 250 / 284.2Syn Z: -0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHRNA1-related multiple pterygium syndrome lethal typeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.81top 10%

GOF

0.82top 10%

LOF

0.1994th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFCloning of twister reveals a novel, dominant gain-of-function mutation in the muscle-specific nicotinic acetylcholine receptor alpha-subunit, CHRNA1.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 15128655 ↗

ClinVar Variant Classifications

591 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic22

VUS276

Likely Benign181

Benign44

Conflicting36

Pathogenic

Likely Pathogenic

276

VUS

181

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	9	5	0	30
Likely Pathogenic	13	8	0	1	22
VUS	4	240	24	8	276
Likely Benign	0	3	74	104	181
Benign	0	1	42	1	44
Conflicting	—				36
Total	33	261	145	114	589

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CHRNA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →