# NM_012414.4(RAB3GAP2):c.303G>A (p.Val101=)

https://sugi.bio/variant/rab3gap2-p-val101

## Summary

**RAB3GAP2 p.Val101= (c.303G>A)** is classified **Uncertain significance** in RAB3GAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-23). Absent from gnomAD v4.1; Associated with Martsolf syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2528727181 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RAB3GAP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Martsolf syndrome.

*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/0025377/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAB3GAP2](https://sugi.bio/atlas/gene/RAB3GAP2/) |
| Protein change (HGVS p.) | p.Val101= |
| Coding change (HGVS c.) | c.303G>A |
| MANE Select transcript | [NM_012414](https://www.ncbi.nlm.nih.gov/nuccore/NM_012414) |
| dbSNP | [rs2528727181](https://www.ncbi.nlm.nih.gov/snp/rs2528727181/) |
| Variant type | single nucleotide variant |
| Location | chr1:220213857-220213857 (GRCh38) |
| ClinVar | [VCV2019320](https://www.ncbi.nlm.nih.gov/clinvar/variation/2019320/) |

**All HGVS expressions:** `NC_000001.10:g.220387199C>T`, `NC_000001.11:g.220213857C>T`, `NG_015837.2:g.63645G>A`, `NM_012414.4:c.303G>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 **donor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.914, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.9**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**.
- Pangolin: Δ**0.32** (gain), gain 0.32 / loss 0.02. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**RAB3GAP2** population constraint: LOEUF 0.535, pLI 0.00071117, missense-Z 1.9223. *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):

- **Warburg micro syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **101** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 79.77, 40% of residues very-high.

**1 experimental structure(s)** (PDB): [8VYB](https://www.rcsb.org/structure/8VYB).

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

*Describes the biological roles of RAB3GAP2 (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:** RAB3GAP2's established molecular role includes small GTPase binding.


### Pathways affected {#pathways}

RAB3GAP2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-independent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811436) | curated |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |

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

**Molecular function:** small GTPase binding.

**Biological process:** establishment of protein localization to endoplasmic reticulum membrane, positive regulation of protein lipidation, positive regulation of endoplasmic reticulum tubular network organization, positive regulation of autophagosome assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-23 |

## Associated conditions {#conditions}

[Martsolf syndrome](https://sugi.bio/atlas/disease/martsolf-syndrome/), [Warburg micro syndrome 2](https://sugi.bio/atlas/disease/warburg-micro-syndrome-2/).

**Reported phenotype names (ClinVar):** Martsolf syndrome, Warburg micro syndrome 2, Congenital cataract with intellectual disability and hypogonadotropic hypogonadism syndrome, MICRO SYNDROME 2.

## Similar variants {#similar}

Related RAB3GAP2 variant pages (same residue, condition, or type): [RAB3GAP2 c.713-2A>C](/variant/rab3gap2-c-713-minus-2a-c), [RAB3GAP2 p.Arg1213Ter](/variant/rab3gap2-p-arg1213ter), [RAB3GAP2 p.Arg426Cys](/variant/rab3gap2-p-arg426cys), [RAB3GAP2 c.*2171A>G](/variant/rab3gap2-c-star-2171a-g), [RAB3GAP2 p.Ala16Thr](/variant/rab3gap2-p-ala16thr), [RAB3GAP2 p.Ala240Pro](/variant/rab3gap2-p-ala240pro), [RAB3GAP2 p.Ala300Thr](/variant/rab3gap2-p-ala300thr), [RAB3GAP2 p.Ala684Glu](/variant/rab3gap2-p-ala684glu).

### 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 2019320). 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.*