# NM_021005.4(NR2F2):c.896_903del (p.Val299fs)

https://sugi.bio/variant/nr2f2-p-val299fs

## Summary

**NR2F2 p.Val299fs (c.896_903del)** is classified **Pathogenic** in NR2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). Associated with Congenital heart disease (variable).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the NR2F2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Congenital heart disease (variable).

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NR2F2](https://sugi.bio/atlas/gene/NR2F2/) |
| Protein change (HGVS p.) | p.Val299fs |
| Coding change (HGVS c.) | c.896_903del |
| MANE Select transcript | [NM_021005](https://www.ncbi.nlm.nih.gov/nuccore/NM_021005) |
| Variant type | Deletion |
| Location | chr15:96334526-96334533 (GRCh38) |
| ClinVar | [VCV3895676](https://www.ncbi.nlm.nih.gov/clinvar/variation/3895676/) |

**All HGVS expressions:** `NC_000015.10:g.96334529_96334536del`, `NC_000015.9:g.96877758_96877765del`, `NG_016753.1:g.13602_13609del`, `NG_132241.1:g.903_910del`, `NM_001145155.2:c.497_504del`, `NM_001145156.1:c.437_444del`, `NM_001145157.2:c.437_444del`, `NM_021005.4:c.896_903del`, `NM_021005.4:c.896_903delTGGAGAAG`

## 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 7.613, GERP 2.68, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.197, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**NR2F2** population constraint: LOEUF 0.197, pLI 1, missense-Z 4.2064; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **NR2F2 related multiple congenital anomalies/dysmorphic syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **299** lies in the nr lbd domain; an α-helix; the 'interaction with zfpm2' region.

AlphaFold model confidence (whole protein): pLDDT 77.94, 53% of residues very-high.

**1 experimental structure(s)** (PDB): [3CJW](https://www.rcsb.org/structure/3CJW).

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

*Describes the biological roles of NR2F2 (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:** NR2F2's established molecular role includes DNA-binding transcription repressor activity, RNA polymerase II-specific. p.Val299fs falls in the nr lbd domain.


### Pathways affected {#pathways}

NR2F2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interaction of NuRD complexes with transcription factors](https://reactome.org/content/detail/R-HSA-9940951) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** DNA-binding transcription repressor activity, RNA polymerase II-specific, retinoic acid binding, DNA-binding transcription factor activity, nuclear receptor activity, protein homodimerization activity, sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of endothelial cell proliferation, female gonad development, negative regulation of endothelial cell migration, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-28 |

## Associated conditions {#conditions}

[Congenital heart disease (variable)](https://sugi.bio/atlas/disease/congenital-heart-disease-variable/).

**Reported phenotype names (ClinVar):** Congenital heart disease (variable).

## Similar variants {#similar}

Related NR2F2 variant pages (same residue, condition, or type): [NR2F2 p.Gly35fs](/variant/nr2f2-p-gly35fs), [NR2F2 p.Asn120fs](/variant/nr2f2-p-asn120fs), [NR2F2 p.Asn229fs](/variant/nr2f2-p-asn229fs), [NR2F2 p.Cys200fs](/variant/nr2f2-p-cys200fs), [NR2F2 p.Cys343fs](/variant/nr2f2-p-cys343fs), [NR2F2 p.Glu214fs](/variant/nr2f2-p-glu214fs), [NR2F2 p.Lys340fs](/variant/nr2f2-p-lys340fs), [NR2F2 p.Pro33fs](/variant/nr2f2-p-pro33fs).

### 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 3895676). 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.*