# NM_015909.4(NBAS):c.248_249dup (p.Val84fs)

https://sugi.bio/variant/nbas-p-val84fs

## Summary

**NBAS p.Val84fs (c.248_249dup)** is classified **Pathogenic** in NBAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). Very rare (popmax 0.005%, amr).

**At a glance:** Pathogenic · review: Single submitter · rsID rs760730197 · 1 submitter · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the NBAS gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [NBAS](https://sugi.bio/atlas/gene/NBAS/) |
| Protein change (HGVS p.) | p.Val84fs |
| Coding change (HGVS c.) | c.248_249dup |
| MANE Select transcript | [NM_015909](https://www.ncbi.nlm.nih.gov/nuccore/NM_015909) |
| dbSNP | [rs760730197](https://www.ncbi.nlm.nih.gov/snp/rs760730197/) |
| Variant type | Duplication |
| Location | chr2:15554098-15554099 (GRCh38) |
| ClinVar | [VCV2881213](https://www.ncbi.nlm.nih.gov/clinvar/variation/2881213/) |

**All HGVS expressions:** `NC_000002.11:g.15694223_15694224dup`, `NC_000002.12:g.15554099_15554100dup`, `NG_032964.1:g.12249_12250dup`, `NM_015909.4:c.248_249dup`, `NR_052013.3:n.278_279dup`

## 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 2.526, GERP -0.717, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.761, pLI 2.4931e-43. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 52**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,984 in the highest group · 3/1,613,930 alleles overall — very rare (popmax 0.005%, amr).

*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}

**NBAS** population constraint: LOEUF 0.761, pLI 2.4931e-43, missense-Z 0.22195; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **84** lies in the 'interaction with use1' region.

AlphaFold model confidence (whole protein): pLDDT 74.42, 4% of residues very-high.

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

*Describes the biological roles of NBAS (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:** NBAS's established molecular role includes SNARE binding. p.Val84fs falls in the interaction with use1 region.


### Pathways affected {#pathways}

NBAS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | curated |

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

**Molecular function:** SNARE binding.

**Biological process:** nuclear-transcribed mRNA catabolic process, retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related NBAS variant pages (same residue, condition, or type): [NBAS p.Gln1282fs](/variant/nbas-p-gln1282fs), [NBAS p.Leu1231fs](/variant/nbas-p-leu1231fs), [NBAS p.Leu1962fs](/variant/nbas-p-leu1962fs), [NBAS p.Leu864fs](/variant/nbas-p-leu864fs), [NBAS p.Thr119fs](/variant/nbas-p-thr119fs), [NBAS p.Tyr142Ter](/variant/nbas-p-tyr142ter), [NBAS c.3072-19dup](/variant/nbas-c-3072-minus-19dup), [NBAS c.3258-5dup](/variant/nbas-c-3258-minus-5dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2881213). 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.*