# NM_018993.4(RIN2):c.1916dup (p.Val641fs)

https://sugi.bio/variant/rin2-p-val641fs

## Summary

**RIN2 p.Val641fs (c.1916dup)** is classified **Pathogenic** in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the RIN2 gene that is reported as disease-causing, but on limited review, 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 | [RIN2](https://sugi.bio/atlas/gene/RIN2/) |
| Protein change (HGVS p.) | p.Val641fs |
| Coding change (HGVS c.) | c.1916dup |
| MANE Select transcript | [NM_018993](https://www.ncbi.nlm.nih.gov/nuccore/NM_018993) |
| Variant type | Duplication |
| Location | chr20:19990158-19990159 (GRCh38) |
| ClinVar | [VCV3645796](https://www.ncbi.nlm.nih.gov/clinvar/variation/3645796/) |

**All HGVS expressions:** `NC_000020.10:g.19970803dup`, `NC_000020.11:g.19990159dup`, `NG_016310.2:g.105594dup`, `NG_016310.3:g.237562dup`, `NM_001242581.2:c.2063dup`, `NM_001378238.1:c.1298dup`, `NM_018993.4:c.1916dup`

## 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 3.367, GERP 3.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.637, pLI 0.0013497. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**RIN2** population constraint: LOEUF 0.637, pLI 0.0013497, missense-Z 0.89466; 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):

- **RIN2 syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **641** lies in the vps9 domain.

AlphaFold model confidence (whole protein): pLDDT 64.30, 22% of residues very-high.

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

*Describes the biological roles of RIN2 (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.*


### Pathways affected {#pathways}

RIN2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |

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

**Biological process:** positive regulation of endothelial cell migration, positive regulation of endothelial cell-matrix adhesion, positive regulation of vasculogenesis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-13 |

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

## Similar variants {#similar}

Related RIN2 variant pages (same residue, condition, or type): [RIN2 p.Leu702fs](/variant/rin2-p-leu702fs), [RIN2 p.Pro225_Pro226insAsnLeuProPro](/variant/rin2-p-pro225-pro226insasnleupropro), [RIN2 c.464-270dup](/variant/rin2-c-464-minus-270dup), [RIN2 c.628+268dup](/variant/rin2-c-628-plus-268dup), [RIN2 c.-36-267_-36-265dup](/variant/rin2-c-minus-36-minus-267-minus-36-minus-265dup), [RIN2 c.-36-2935dup](/variant/rin2-c-minus-36-minus-2935dup), [RIN2 c.-36-2936_-36-2935dup](/variant/rin2-c-minus-36-minus-2936-minus-36-minus-2935dup), [RIN2 p.Pro309fs](/variant/rin2-p-pro309fs).

### 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 3645796). 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.*