ANO4

protein-coding

anoctamin 4, the group of Anoctamins

Gene summary

Enables intracellularly calcium-gated chloride channel activity. Involved in chloride transmembrane transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

TMEM16D

MANE transcript

NM_001286615.2

Inheritance

ClinVar variants

P:7U:102B:2

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr12:100,717,526-101,128,641

External References & Databases

Ensembl (ENSG00000151572)

Transcript & Mutation Effects

hg38 • Region Span ~411.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANO4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 90

not providedTotal: 6

Developmental and epileptic encephalopathyTotal: 6

ANO4-related disorderTotal: 2

Temporal lobe epilepsyTotal: 1

Generalized epilepsy with febrile seizures plusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001286615.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar		1 clinvar	2
missense	6 clinvar	1 clinvar	99 clinvar	1 clinvar		107
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	6	1	102	1	1	111

Highest pathogenic variant AF is 0.000003727236

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001286615.2	RefSeq	NP_001273544.1	26	MANE Select
ENST00000392977.8	Ensembl	ENSP00000376703.3	26	MANE Select
NM_001286616.1	RefSeq	NP_001273545.1	26	Standard
NM_178826.4	RefSeq	NP_849148.2	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

chloride transport
ion transmembrane transport
calcium activated phosphatidylserine scrambling
calcium activated phosphatidylcholine scrambling
calcium activated galactosylceramide scrambling

Molecular Function

intracellular calcium activated chloride channel activity
phospholipid scramblase activity
protein dimerization activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392979
Coding exons: 25
Length: 411116
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.53	344	504	0.682	0.0000266	6070
Missense (PolyPhen)		157	230.72	0.68049		2741
Synonymous	2.04	141	175	0.804	0.00000930	1648
Loss of Function	5.20	19	63.8	0.298	0.00000369	695

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00039	0.00032	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.000069	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide. Does not exhibit calcium-activated chloride channel (CaCC) activity. {ECO:0000250|UniProtKB:Q8C5H1}.;

Recessive Scores

pRec: 0.133

Intolerance Scores

LoFtool: 0.811
RVIS EVS: -0.78
RVIS percentile EVS: 12.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0483

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium