CHRNA4

Chr 20AD

cholinergic receptor nicotinic alpha 4 subunit

Also known as: BFNC, EBN, EBN1, NACHR, NACHRA4, NACRA4

NCBI Gene: 1137 ENSG00000101204 UniProt: P43681 OMIM: 118504

This gene encodes the α4 subunit of neuronal nicotinic acetylcholine receptors, which are pentameric ligand-gated cation channels that mediate excitatory synaptic transmission in the central nervous system. Mutations cause autosomal dominant nocturnal frontal lobe epilepsy type 1, a seizure disorder typically beginning in childhood or adolescence with brief nocturnal seizures arising from the frontal lobe. The gene shows low constraint to loss-of-function variation (pLI = 0.00009, LOEUF = 0.822), consistent with autosomal dominant inheritance where heterozygous mutations are pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.822 OMIM phenotypes

Clinical Summary— CHRNA4

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Gene-Disease Validity (ClinGen)

familial sleep-related hypermotor epilepsy · ADDefinitive

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

17 unique Pathogenic / Likely Pathogenic· 477 VUS of 1179 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHRNA4

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?

0.82LOEUF

pLI 0.000

Z-score 2.17

OE 0.48 (0.30–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.34Z-score

OE missense 0.95 (0.87–1.04)

377 obs / 396.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.30–0.82)

0≤0.351.4

Missense OE?0.95 (0.87–1.04)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 10 / 20.6Missense obs/exp: 377 / 396.1Syn Z: -2.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCHRNA4-related nocturnal frontal lobe epilepsyGOFAD

This gene — mechanism propensity

0.83top 10%

GOF

0.84top 5%

LOF

0.2387th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFIncreased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release.1

LOFHaploinsufficiency for CHRNA4 and ARFGAP1 may have contributed towards a severe phenotype.2

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

References

ClinVar Variant Classifications

1179 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic5

VUS477

Likely Benign448

Benign101

Conflicting128

Pathogenic

Likely Pathogenic

477

VUS

448

Likely Benign

101

Benign

128

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	9	0	12
Likely Pathogenic	1	4	0	0	5
VUS	34	411	26	6	477
Likely Benign	4	73	94	277	448
Benign	0	1	87	13	101
Conflicting	—				128
Total	39	492	216	296	1,171

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 95) ClinVar copy-number / structural variants overlap CHRNA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →