NOVA2

protein-coding

NOVA alternative splicing regulator 2

Gene summary

Enables sequence-specific mRNA binding activity. Involved in neuron differentiation and regulation of alternative mRNA splicing, via spliceosome. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

NOVA3

MANE transcript

NM_002516.4

Inheritance

ClinVar variants

P:13U:85B:30

Top phenotype

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:45,933,734-45,974,044

External References & Databases

Ensembl (ENSG00000104967)

Transcript & Mutation Effects

hg38 • Region Span ~40.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030024

Submitter: Ambry Genetics

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030024

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *NOVA2* gene encodes a neuronal RNA-binding protein that plays a crucial role in regulating alternative mRNA splicing. *NOVA2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Mattioli et al., PMID: 32197073). Affected individuals present with global developmental delay, intellectual disability, significantly impaired speech, facial dysmorphism, hypotonia, spasticity or gait ataxia, and behavioral abnormalities including autism spectrum disorder or autistic features. Some individuals exhibit behaviors reminiscent of Angelman syndrome, such as frequent laughter and attraction to water. Additional features include progressive microcephaly, seizures, and structural brain abnormalities. Thirteen truncating variants (12 frameshift, 1 nonsense) that have been reported in 13 probands in two publications (PMIDs: 32197073, 35607920) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants were *de novo* in all instances in which parental DNA was available. All the frameshift variants are located in the last exon and are predicted to escape nonsense-mediated mRNA decay. Ten frameshift variants cluster between residues 237 and 276, and replace the KH3 RNA-binding domain by a similar alternative C-terminal sequence. The mechanism of pathogenicity is hypothesized to be partial loss-of-function (hypomorphic) rather than haploinsufficiency, although a possible gain-of-function effect of the new C-terminal extension cannot be excluded (PMID: 32197073). This gene-disease relationship is also supported by experimental evidence, including mouse and zebrafish models, and functional alterations in non-patient cells. In summary, there is definitive evidence supporting the relationship between *NOVA2* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 15, 2024 (SOP Version 11).

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030024

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030024

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32197073

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NOVA2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 59

Inborn genetic diseasesTotal: 40

NOVA2-related disorderTotal: 20

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalitiesTotal: 19

not specifiedTotal: 14

Severe intellectual disabilityTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002516.4. 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	24 clinvar		25
missense			75 clinvar	6 clinvar		81
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift	10 clinvar	3 clinvar	4 clinvar			17
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	10	3	85	30	0	128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002516.4	RefSeq	NP_002507.1	4	MANE Select
ENST00000263257.6	Ensembl	ENSP00000263257.4	4	MANE Select
ENST00000596784.1	Ensembl	ENSP00000471736.1	2	Standard
ENST00000676183.1	Ensembl	ENSP00000501708.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mRNA splicing, via spliceosome
regulation of RNA metabolic process
negative regulation of cold-induced thermogenesis

Molecular Function

RNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263257
Coding exons: 4
Length: 39813
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.35	70	272	0.258	0.0000188	3065
Missense (PolyPhen)		5	43.214	0.1157		377
Synonymous	2.88	96	139	0.690	0.0000113	1115
Loss of Function	3.25	0	12.3	0.00	6.16e-7	149

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May regulate RNA splicing or metabolism in a specific subset of developing neurons (By similarity). Binds single strand RNA. {ECO:0000250}.;

Intolerance Scores

RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.201

Gene Damage Prediction

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