# NM_002516.4(NOVA2):c.709_748del (p.Val237fs)

https://sugi.bio/variant/nova2-p-val237fs

## Summary

**NOVA2 p.Val237fs (c.709_748del)** is classified **Pathogenic** in NOVA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-30). No gnomAD frequency available for this variant; Associated with neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1967739365 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NOVA2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027922/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NOVA2](https://sugi.bio/atlas/gene/NOVA2/) |
| Protein change (HGVS p.) | p.Val237fs |
| Coding change (HGVS c.) | c.709_748del |
| MANE Select transcript | [NM_002516](https://www.ncbi.nlm.nih.gov/nuccore/NM_002516) |
| dbSNP | [rs1967739365](https://www.ncbi.nlm.nih.gov/snp/rs1967739365/) |
| Variant type | Deletion |
| Location | chr19:45940594-45940633 (GRCh38) |
| ClinVar | [VCV870457](https://www.ncbi.nlm.nih.gov/clinvar/variation/870457/) |

**All HGVS expressions:** `NC_000019.10:g.45940595_45940634del`, `NC_000019.9:g.46443853_46443892del`, `NM_002516.4:c.709_748del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 10.931, GERP 2.58, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.611, pLI 0.85257. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((CGG)n). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**NOVA2** population constraint: LOEUF 0.611, pLI 0.85257, missense-Z 2.5337. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.60, 22% of residues very-high.

**2 experimental structure(s)** (PDB): [1DTJ](https://www.rcsb.org/structure/1DTJ), [1EC6](https://www.rcsb.org/structure/1EC6).

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

*Describes the biological roles of NOVA2 (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:** NOVA2's established molecular role includes RNA binding.


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

**Molecular function:** RNA binding, sequence-specific mRNA binding.

**Biological process:** regulation of alternative mRNA splicing, via spliceosome, neuron differentiation, regulation of RNA metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-04-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2020-04-30 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-or-without-autistic-features-and-or-structural-brain-abnormalities/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities.

## Similar variants {#similar}

Related NOVA2 variant pages (same residue, condition, or type): [NOVA2 p.Gly219fs](/variant/nova2-p-gly219fs), [NOVA2 p.Leu175fs](/variant/nova2-p-leu175fs), [NOVA2 p.Tyr330fs](/variant/nova2-p-tyr330fs), [NOVA2 p.Val261fs](/variant/nova2-p-val261fs), [NOVA2 c.41_85+14del](/variant/nova2-c-41-85-plus-14del), [NOVA2 p.Ala314_Ala316del](/variant/nova2-p-ala314-ala316del), [NOVA2 p.Val237Ala](/variant/nova2-p-val237ala), [NOVA2 p.Ala287=](/variant/nova2-p-ala287).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 870457). 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.*