# NM_004738.5(VAPB):c.597G>A (p.Arg199=)

https://sugi.bio/variant/vapb-p-arg199

## Summary

**VAPB p.Arg199= (c.597G>A)** is classified **Likely benign** in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). Very rare (popmax 0.00223%, eas); Associated with amyotrophic lateral sclerosis type 8.

**At a glance:** Likely benign · review: Single submitter · rsID rs748793394 · 1 submitter · 2 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the VAPB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to amyotrophic lateral sclerosis type 8.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010499/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VAPB](https://sugi.bio/atlas/gene/VAPB/) |
| Protein change (HGVS p.) | p.Arg199= |
| Coding change (HGVS c.) | c.597G>A |
| MANE Select transcript | [NM_004738](https://www.ncbi.nlm.nih.gov/nuccore/NM_004738) |
| dbSNP | [rs748793394](https://www.ncbi.nlm.nih.gov/snp/rs748793394/) |
| Variant type | single nucleotide variant |
| Location | chr20:58444100-58444100 (GRCh38) |
| ClinVar | [VCV1127531](https://www.ncbi.nlm.nih.gov/clinvar/variation/1127531/) |

**All HGVS expressions:** `LRG_656:g.59912G>A`, `NC_000020.10:g.57019156G>A`, `NC_000020.11:g.58444100G>A`, `NG_008073.2:g.59912G>A`, `NM_001195677.2:c.235G>A`, `NM_004738.5:c.597G>A`, `NR_036633.2:n.643G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.901, GERP 0.552, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.445**. 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 deltas (raw): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.24** (loss), gain 0.00 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.00103% · FAF99 0.00083% · 1/44,904 in the highest group · 21/1,614,110 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,904 |
| European (non-Finnish) | 0.00161% | 62,108 |
| African / African-American | 0.00133% | 74,926 |

*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}

**VAPB** population constraint: LOEUF 0.699, pLI 0.52375, missense-Z 0.69832. *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):

- **amyotrophic lateral sclerosis type 8** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.45, 40% of residues very-high.

**3 experimental structure(s)** (PDB): [2MDK](https://www.rcsb.org/structure/2MDK), [3IKK](https://www.rcsb.org/structure/3IKK), [9WGH](https://www.rcsb.org/structure/9WGH).

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

*Describes the biological roles of VAPB (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:** VAPB's established molecular role includes microtubule binding.


### Pathways affected {#pathways}

VAPB participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [Sphingolipid de novo biosynthesis](https://reactome.org/content/detail/R-HSA-1660661) | curated |

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

**Molecular function:** microtubule binding, enzyme binding, FFAT motif binding, protein homodimerization activity, cadherin binding, protein heterodimerization activity.

**Biological process:** intracellular calcium ion homeostasis, endoplasmic reticulum to Golgi vesicle-mediated transport, endoplasmic reticulum organization, viral release from host cell, cholesterol transport, endoplasmic reticulum unfolded protein response.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-10.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-10 |

## Associated conditions {#conditions}

[amyotrophic lateral sclerosis type 8](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-8/), [adult-onset proximal spinal muscular atrophy, autosomal dominant](https://sugi.bio/atlas/disease/adult-onset-proximal-spinal-muscular-atrophy-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Amyotrophic lateral sclerosis type 8, Adult-onset proximal spinal muscular atrophy, autosomal dominant, FINKEL LATE-ADULT TYPE SMA, Spinal muscular atrophy, late-onset, finkel type.

## Similar variants {#similar}

Related VAPB variant pages (same residue, condition, or type): [VAPB p.Pro56Ser](/variant/vapb-p-pro56ser), [VAPB p.Ala104Thr](/variant/vapb-p-ala104thr), [VAPB p.Arg182Lys](/variant/vapb-p-arg182lys), [VAPB p.Asp163Asn](/variant/vapb-p-asp163asn), [VAPB p.Asp24Asn](/variant/vapb-p-asp24asn), [VAPB p.Asp37Glu](/variant/vapb-p-asp37glu), [VAPB p.Asp62Asn](/variant/vapb-p-asp62asn), [VAPB p.Asp77Asn](/variant/vapb-p-asp77asn).

### 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 1127531). 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.*