# NM_018993.4(RIN2):c.673C>T (p.Pro225Ser)

https://sugi.bio/variant/rin2-p-pro225ser

## Summary

**RIN2 p.Pro225Ser (c.673C>T)** is classified **Uncertain significance** in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-05). AlphaMissense: likely benign (0.081); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2515504607 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the RIN2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Pro225Ser |
| Coding change (HGVS c.) | c.673C>T |
| MANE Select transcript | [NM_018993](https://www.ncbi.nlm.nih.gov/nuccore/NM_018993) |
| dbSNP | [rs2515504607](https://www.ncbi.nlm.nih.gov/snp/rs2515504607/) |
| Variant type | single nucleotide variant |
| Location | chr20:19974698-19974698 (GRCh38) |
| ClinVar | [VCV2258976](https://www.ncbi.nlm.nih.gov/clinvar/variation/2258976/) |

**All HGVS expressions:** `NC_000020.10:g.19955342C>T`, `NC_000020.11:g.19974698C>T`, `NG_016310.2:g.90133C>T`, `NG_016310.3:g.222101C>T`, `NM_001242581.2:c.820C>T`, `NM_001378238.1:c.55C>T`, `NM_018993.4:c.673C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.081)
- REVEL 0.054 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.151 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.792, GERP 1.38, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.1**. 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.*
- Regional missense constraint: **o/e 1.06** across the covering region of the MANE Select transcript (19,889,602–19,975,556), spanning 85,954 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.78 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.*
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.15. SpliceAI below 0.2. 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 (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,024 in the highest group · 1/1,613,910 alleles overall — very rare (popmax 0.00167%, amr).

*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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-05 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## 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.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), [RIN2 p.Arg446Gln](/variant/rin2-p-arg446gln).

### 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 2258976). 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.*