# NM_015909.4(NBAS):c.1741C>T (p.Arg581Ter)

https://sugi.bio/variant/nbas-p-arg581ter

## Summary

**NBAS p.Arg581Ter (c.1741C>T)** is classified **Pathogenic/Likely pathogenic** in NBAS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Very rare (popmax 0.00446%, eas); Associated with NBAS-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs767280377 · 4 submitters · 3 linked conditions · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the NBAS gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to NBAS-related disorder.

*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.Arg581Ter |
| Coding change (HGVS c.) | c.1741C>T |
| MANE Select transcript | [NM_015909](https://www.ncbi.nlm.nih.gov/nuccore/NM_015909) |
| dbSNP | [rs767280377](https://www.ncbi.nlm.nih.gov/snp/rs767280377/) |
| Variant type | single nucleotide variant |
| Location | chr2:15468518-15468518 (GRCh38) |
| ClinVar | [VCV976858](https://www.ncbi.nlm.nih.gov/clinvar/variation/976858/) |

**All HGVS expressions:** `NC_000002.11:g.15608642G>A`, `NC_000002.12:g.15468518G>A`, `NG_032964.1:g.97831C>T`, `NM_015909.4:c.1741C>T`, `NR_052013.3:n.1771C>T`

## 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 6.581, GERP 1.05, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 17 of 52**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.00138% · FAF99 0.00116% · 2/44,872 in the highest group · 30/1,613,802 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| East Asian (grpmax) | 0.00446% | 22,436 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,239 |
| European (non-Finnish) | 0.00203% | 49,163 |
| South Asian | 0.0011% | 91,080 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **581** 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.Arg581Ter 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Pathogenic).

**Submission history:** 4 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genomics Laboratory, Stanford Medicine | Likely pathogenic | no assertion criteria provided | clinical testing | 2020-07-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |

## Associated conditions {#conditions}

[NBAS-related disorder](https://sugi.bio/atlas/disease/nbas-related-disorder/), [short stature-optic atrophy-Pelger-Huët anomaly syndrome](https://sugi.bio/atlas/disease/short-stature-optic-atrophy-pelger-hu-t-anomaly-syndrome/), [infantile liver failure syndrome 2](https://sugi.bio/atlas/disease/infantile-liver-failure-syndrome-2/).

**Reported phenotype names (ClinVar):** NBAS-related disorder, Infantile liver failure syndrome 2, Short stature-optic atrophy-Pelger-Huët anomaly syndrome, not provided, Fetal anomalies with a likely genetic cause, none provided, NBAS-related condition, Short stature, optic nerve atrophy, and Pelger-Huet anomaly, Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome.

## Similar variants {#similar}

Related NBAS variant pages (same residue, condition, or type): [NBAS p.Arg581Gln](/variant/nbas-p-arg581gln), [NBAS p.Arg581Leu](/variant/nbas-p-arg581leu), [NBAS c.173-2A>G](/variant/nbas-c-173-minus-2a-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.4583-2A>G](/variant/nbas-c-4583-minus-2a-g), [NBAS c.513+2T>C](/variant/nbas-c-513-plus-2t-c), [NBAS c.886-5T>A](/variant/nbas-c-886-minus-5t-a).

### 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 976858). 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.*