# NM_012233.3(RAB3GAP1):c.264_270delinsTTATTA (p.Lys89fs)

https://sugi.bio/variant/rab3gap1-p-lys89fs

## Summary

**RAB3GAP1 p.Lys89fs (c.264_270delinsTTATTA)** is classified **Pathogenic** in RAB3GAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2010-10-01). No gnomAD frequency available for this variant; Associated with Warburg micro syndrome 1.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs730882184 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RAB3GAP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Warburg micro syndrome 1.

*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/0024758/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAB3GAP1](https://sugi.bio/atlas/gene/RAB3GAP1/) |
| Protein change (HGVS p.) | p.Lys89fs |
| Coding change (HGVS c.) | c.264_270delinsTTATTA |
| MANE Select transcript | [NM_012233](https://www.ncbi.nlm.nih.gov/nuccore/NM_012233) |
| dbSNP | [rs730882184](https://www.ncbi.nlm.nih.gov/snp/rs730882184/) |
| Variant type | Indel |
| Location | chr2:135091111-135091117 (GRCh38) |
| ClinVar | [VCV7062](https://www.ncbi.nlm.nih.gov/clinvar/variation/7062/) |

**All HGVS expressions:** `NC_000002.11:g.135848681_135848687delinsTTATTA`, `NC_000002.12:g.135091111_135091117delinsTTATTA`, `NG_016972.1:g.43847_43853delinsTTATTA`, `NM_001172435.2:c.264_270delinsTTATTA`, `NM_012233.3:c.264_270delinsTTATTA`

## 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 2.371, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.798, pLI 5.1538e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**RAB3GAP1** population constraint: LOEUF 0.798, pLI 5.1538e-17, missense-Z 2.0402; 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.*

Curated gene–disease validity (ClinGen):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.46, 47% 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 RAB3GAP1 (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:** RAB3GAP1's established molecular role includes guanyl-nucleotide exchange factor activity.


### Pathways affected {#pathways}

RAB3GAP1 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:** guanyl-nucleotide exchange factor activity, GTPase activator activity, small GTPase binding.

**Biological process:** brain development, hypothalamus development, lipid droplet organization, camera-type eye development, face morphogenesis, establishment of protein localization to endoplasmic reticulum membrane.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2010-10-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2010-10-01 |

## Associated conditions {#conditions}

[Warburg micro syndrome 1](https://sugi.bio/atlas/disease/warburg-micro-syndrome-1/).

**Reported phenotype names (ClinVar):** Warburg micro syndrome 1.

## Similar variants {#similar}

Related RAB3GAP1 variant pages (same residue, condition, or type): [RAB3GAP1 p.Lys89=](/variant/rab3gap1-p-lys89), [RAB3GAP1 p.Met729_Lys730delinsIleTer](/variant/rab3gap1-p-met729-lys730delinsileter), [RAB3GAP1 c.2607-1G>C](/variant/rab3gap1-c-2607-minus-1g-c), [RAB3GAP1 c.748+1G>A](/variant/rab3gap1-c-748-plus-1g-a), [RAB3GAP1 c.899+1G>A](/variant/rab3gap1-c-899-plus-1g-a), [RAB3GAP1 p.Arg187Ter](/variant/rab3gap1-p-arg187ter), [RAB3GAP1 p.Arg337Ter](/variant/rab3gap1-p-arg337ter), [RAB3GAP1 p.Arg347Ter](/variant/rab3gap1-p-arg347ter).

### 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 7062). 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.*