# NM_018993.4(RIN2):c.2220C>T (p.Ser740=)

https://sugi.bio/variant/rin2-p-ser740

## Summary

**RIN2 p.Ser740= (c.2220C>T)** is classified **Benign/Likely benign** in RIN2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Rare (popmax 0.245%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs146810222 · 4 submitters · rare (popmax 0.245%, afr)

## For patients & families {#patients}

This is a change in the RIN2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters.

*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.Ser740= |
| Coding change (HGVS c.) | c.2220C>T |
| MANE Select transcript | [NM_018993](https://www.ncbi.nlm.nih.gov/nuccore/NM_018993) |
| dbSNP | [rs146810222](https://www.ncbi.nlm.nih.gov/snp/rs146810222/) |
| Variant type | single nucleotide variant |
| Location | chr20:19996698-19996698 (GRCh38) |
| ClinVar | [VCV696797](https://www.ncbi.nlm.nih.gov/clinvar/variation/696797/) |

**All HGVS expressions:** `NC_000020.10:g.19977342C>T`, `NC_000020.11:g.19996698C>T`, `NG_016310.2:g.112133C>T`, `NM_001242581.2:c.2367C>T`, `NM_001378238.1:c.1602C>T`, `NM_018993.4:c.2220C>T`

## 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 -10.766, GERP -7.42 — fast-evolving / accelerated position
- CADD: **PHRED 1.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.22 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.245%** (afr) · FAF95 0.216% · FAF99 0.205% · 184/75,054 in the highest group · 241/1,614,024 alleles overall — rare (popmax 0.245%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.245% | 408 |
| Admixed American | 0.0383% | 2,610 |
| South Asian | 0.0198% | 5,060 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,943 |
| European (non-Finnish) | 0.000509% | 196,648 |

*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 **740** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-11 |

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

## Similar variants {#similar}

Related RIN2 variant pages (same residue, condition, or type): [RIN2 p.Ala205Val](/variant/rin2-p-ala205val), [RIN2 p.Ala72Thr](/variant/rin2-p-ala72thr), [RIN2 p.Ala8Thr](/variant/rin2-p-ala8thr), [RIN2 p.Arg135Cys](/variant/rin2-p-arg135cys), [RIN2 p.Arg170Trp](/variant/rin2-p-arg170trp), [RIN2 p.Arg255Thr](/variant/rin2-p-arg255thr), [RIN2 p.Arg290Leu](/variant/rin2-p-arg290leu), [RIN2 p.Arg303Gln](/variant/rin2-p-arg303gln).

### 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 696797). 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.*