# NM_004637.6(RAB7A):c.*165AC[9]

https://sugi.bio/variant/rab7a-c-star-165ac-9

## Summary

**RAB7A c.*165AC[9]** is classified **Likely benign** in RAB7A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-13). Low-frequency (popmax 1.87%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs3830294 · 1 submitter · low-frequency (popmax 1.87%, eas)

## For patients & families {#patients}

This is a change in the RAB7A gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [RAB7A](https://sugi.bio/atlas/gene/RAB7A/) |
| Coding change (HGVS c.) | c.*165AC[9] |
| MANE Select transcript | [NM_004637](https://www.ncbi.nlm.nih.gov/nuccore/NM_004637) |
| dbSNP | [rs3830294](https://www.ncbi.nlm.nih.gov/snp/rs3830294/) |
| Variant type | Microsatellite |
| Location | chr3:128813585-128813586 (GRCh38) |
| ClinVar | [VCV1213456](https://www.ncbi.nlm.nih.gov/clinvar/variation/1213456/) |

**All HGVS expressions:** `LRG_266:g.92452AC[9]`, `NC_000003.11:g.128532430AC[9]`, `NC_000003.12:g.128813587AC[9]`, `NG_008070.1:g.92452AC[9]`, `NM_004637.6:c.*165AC[9]`

## 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 -1.721, phastCons 0.009 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.424**. 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.*
- Non-coding constraint (Gnocchi): **Z 1.04**, o/e 0.93 (1 kb window 128,813,000–128,814,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((CA)n, CA). The alignment of this microsatellite is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **1.87%** (eas) · FAF95 1.75% · FAF99 1.7% · 611/32,682 in the highest group · 2,117/628,322 alleles overall — low-frequency (popmax 1.87%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.87% | 53 |
| African / African-American | 1.33% | 75 |
| Remaining individuals (not grpmax-eligible) | 0.298% | 336 |
| South Asian | 0.252% | 397 |
| Middle Eastern | 0.175% | 572 |
| Admixed American | 0.163% | 615 |
| European (non-Finnish) | 0.126% | 796 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.07% | 1,428 |
| Finnish (not grpmax-eligible) | 0.0432% | 2,317 |

*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}

**RAB7A** population constraint: LOEUF 0.242, pLI 0.99995, missense-Z 3.3709. *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):

- **Charcot-Marie-Tooth disease type 2** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.98, 70% of residues very-high.

**10 experimental structure(s)** (PDB): [1T91](https://www.rcsb.org/structure/1T91), [1YHN](https://www.rcsb.org/structure/1YHN), [3LAW](https://www.rcsb.org/structure/3LAW), [6IYB](https://www.rcsb.org/structure/6IYB), [6WCW](https://www.rcsb.org/structure/6WCW), [7F6J](https://www.rcsb.org/structure/7F6J) — incl. mutant structure 3LAW.

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

*Describes the biological roles of RAB7A (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:** RAB7A's established molecular role includes GTPase activity. In Reactome, RAB7A is annotated in disease pathway(s) including **Prevention of phagosomal-lysosomal fusion**, **Suppression of autophagy**.

**Disease mechanism (Reactome):** RAB7A loss or alteration is curated in [Prevention of phagosomal-lysosomal fusion](https://reactome.org/content/detail/R-HSA-9636383), [Suppression of autophagy](https://reactome.org/content/detail/R-HSA-9636569).

### Pathways affected {#pathways}

RAB7A participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Prevention of phagosomal-lysosomal fusion](https://reactome.org/content/detail/R-HSA-9636383) | curated |
| ⚕ [Suppression of autophagy](https://reactome.org/content/detail/R-HSA-9636569) | curated |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |
| [RAB geranylgeranylation](https://reactome.org/content/detail/R-HSA-8873719) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOF GTPase cycle](https://reactome.org/content/detail/R-HSA-9035034) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [TBC/RABGAPs](https://reactome.org/content/detail/R-HSA-8854214) | curated |

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

**Molecular function:** GTPase activity, G protein activity, GTP binding, GDP binding, retromer complex binding.

**Biological process:** autophagosome assembly, protein targeting to lysosome, epidermal growth factor catabolic process, endosome to lysosome transport, response to bacterium, viral release from host cell.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-13 |

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

## Similar variants {#similar}

Related RAB7A variant pages (same residue, condition, or type): [RAB7A c.400-13CTT[2]](/variant/rab7a-c-400-minus-13ctt-2), [RAB7A c.-70CTC[2]](/variant/rab7a-c-minus-70ctc-2), [RAB7A c.*165AC[7]](/variant/rab7a-c-star-165ac-7), [RAB7A c.*182CA[9]](/variant/rab7a-c-star-182ca-9).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1213456). 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.*