# NM_015909.4(NBAS):c.1686G>A (p.Arg562=)

https://sugi.bio/variant/nbas-p-arg562

## Summary

**NBAS p.Arg562= (c.1686G>A)** is classified **Likely benign** in NBAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs200878036 · 2 submitters · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the NBAS gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Arg562= |
| Coding change (HGVS c.) | c.1686G>A |
| MANE Select transcript | [NM_015909](https://www.ncbi.nlm.nih.gov/nuccore/NM_015909) |
| dbSNP | [rs200878036](https://www.ncbi.nlm.nih.gov/snp/rs200878036/) |
| Variant type | single nucleotide variant |
| Location | chr2:15473261-15473261 (GRCh38) |
| ClinVar | [VCV2060319](https://www.ncbi.nlm.nih.gov/clinvar/variation/2060319/) |

**All HGVS expressions:** `NC_000002.11:g.15613385C>T`, `NC_000002.12:g.15473261C>T`, `NG_032964.2:g.93073G>A`, `NM_015909.4:c.1686G>A`, `NR_052013.3:n.1716G>A`

## Computational & population evidence {#evidence}

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

- **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 0.265, GERP -1.17, phastCons 0.978 — weakly conserved position
- CADD: **PHRED 7.877**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.27 donor gain), 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 **0.0165%** (mid) · FAF95 0.000292% · FAF99 0.000211% · 1/6,062 in the highest group · 9/1,614,136 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| European (non-Finnish) | 0.000678% | 147,498 |

*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 **562** lies in a UniProt-annotated variant site (in ilfs2; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; 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.Arg562= 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-12.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-12 |

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

## Similar variants {#similar}

Related NBAS variant pages (same residue, condition, or type): [NBAS c.1726-2A>G](/variant/nbas-c-1726-minus-2a-g), [NBAS c.173-2A>G](/variant/nbas-c-173-minus-2a-g), [NBAS c.209+2T>G](/variant/nbas-c-209-plus-2t-g), [NBAS c.2423+404G>C](/variant/nbas-c-2423-plus-404g-c), [NBAS c.335+1G>C](/variant/nbas-c-335-plus-1g-c), [NBAS c.4461+2T>C](/variant/nbas-c-4461-plus-2t-c), [NBAS c.4583-2A>G](/variant/nbas-c-4583-minus-2a-g), [NBAS c.513+2T>C](/variant/nbas-c-513-plus-2t-c).

### 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 2026-10-14); 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 2060319). 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.*