# NM_015909.4(NBAS):c.1084C>T (p.Pro362Ser)

https://sugi.bio/variant/nbas-p-pro362ser

## Summary

**NBAS p.Pro362Ser (c.1084C>T)** is classified **Uncertain significance** in NBAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.6264); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs779602732 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00034%, nfe)

## For patients & families {#patients}

This is a change in the NBAS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Pro362Ser |
| Coding change (HGVS c.) | c.1084C>T |
| MANE Select transcript | [NM_015909](https://www.ncbi.nlm.nih.gov/nuccore/NM_015909) |
| dbSNP | [rs779602732](https://www.ncbi.nlm.nih.gov/snp/rs779602732/) |
| Variant type | single nucleotide variant |
| Location | chr2:15478289-15478289 (GRCh38) |
| ClinVar | [VCV1968189](https://www.ncbi.nlm.nih.gov/clinvar/variation/1968189/) |

**All HGVS expressions:** `NC_000002.11:g.15618413G>A`, `NC_000002.12:g.15478289G>A`, `NG_032964.1:g.88060C>T`, `NG_032964.2:g.88045C>T`, `NM_015909.2:c.1084C>T`, `NM_015909.4:c.1084C>T`, `NR_052013.3:n.1114C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6264)
- REVEL 0.395 (indeterminate)
- SaProt LLR -9.699 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 11.849, GERP 1.9, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.03** across the covering region of the MANE Select transcript (15,167,051–15,561,304), spanning 394,253 bp. Chi-square p 0.09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.59 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,175,240 in the highest group · 4/1,456,352 alleles overall — very rare (popmax 0.00034%, nfe).

*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 30, triplosensitivity Not yet evaluated (0–3 scale). *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 **362** lies in a UniProt-annotated variant site (in ilfs2; uncertain significance); 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.Pro362Ser 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-08.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-08 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related NBAS variant pages (same residue, condition, or type): [NBAS p.Ala1568Val](/variant/nbas-p-ala1568val), [NBAS p.Ala1645Val](/variant/nbas-p-ala1645val), [NBAS p.Ala1795Val](/variant/nbas-p-ala1795val), [NBAS p.Ala1941Gly](/variant/nbas-p-ala1941gly), [NBAS p.Ala195Thr](/variant/nbas-p-ala195thr), [NBAS p.Ala2005Thr](/variant/nbas-p-ala2005thr), [NBAS p.Ala2341Val](/variant/nbas-p-ala2341val), [NBAS p.Ala48Ser](/variant/nbas-p-ala48ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1968189). 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.*