# NM_021930.6(RINT1):c.177C>T (p.Phe59=)

https://sugi.bio/variant/rint1-p-phe59

## Summary

**RINT1 p.Phe59= (c.177C>T)** is classified **Likely benign** in RINT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-29). Ultra-rare (popmax 0.0153%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs138894974 · 2 submitters · ultra-rare (popmax 0.0153%, nfe)

## For patients & families {#patients}

This is a change in the RINT1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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 | [RINT1](https://sugi.bio/atlas/gene/RINT1/) |
| Protein change (HGVS p.) | p.Phe59= |
| Coding change (HGVS c.) | c.177C>T |
| MANE Select transcript | [NM_021930](https://www.ncbi.nlm.nih.gov/nuccore/NM_021930) |
| dbSNP | [rs138894974](https://www.ncbi.nlm.nih.gov/snp/rs138894974/) |
| Variant type | single nucleotide variant |
| Location | chr7:105536653-105536653 (GRCh38) |
| ClinVar | [VCV700586](https://www.ncbi.nlm.nih.gov/clinvar/variation/700586/) |

**All HGVS expressions:** `NC_000007.13:g.105177100C>T`, `NC_000007.14:g.105536653C>T`, `NG_051951.1:g.9573C>T`, `NM_001346599.2:c.39+41C>T`, `NM_001346600.2:c.-843C>T`, `NM_001346601.2:c.-746C>T`, `NM_001346603.2:c.-366C>T`, `NM_021930.6:c.177C>T`, `NR_144478.2:n.292C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.833, GERP 2.04, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.85**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.02**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.02**.
- Population frequency (gnomAD v4.1): grpmax **0.0153%** (nfe) · FAF95 0.0134% · FAF99 0.0127% · 180/1,178,776 in the highest group · 183/1,612,208 alleles overall — ultra-rare (popmax 0.0153%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0153% | 6,549 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,805 |

*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}

**RINT1** population constraint: LOEUF 0.931, pLI 3.8414e-15, missense-Z 0.92023; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.97, 63% of residues very-high.

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

*Describes the biological roles of RINT1 (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}

RINT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | other |

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

**Biological process:** mitotic G2 DNA damage checkpoint signaling, regulation of ER to Golgi vesicle-mediated transport.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-29.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-29 |

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

## Similar variants {#similar}

Related RINT1 variant pages (same residue, condition, or type): [RINT1 p.Phe59Leu](/variant/rint1-p-phe59leu), [RINT1 c.1107+1G>T](/variant/rint1-c-1107-plus-1g-t), [RINT1 c.1886+5G>A](/variant/rint1-c-1886-plus-5g-a), [RINT1 c.516-3C>T](/variant/rint1-c-516-minus-3c-t), [RINT1 c.840-12T>A](/variant/rint1-c-840-minus-12t-a), [RINT1 c.840-3C>G](/variant/rint1-c-840-minus-3c-g), [RINT1 p.Ala138Thr](/variant/rint1-p-ala138thr), [RINT1 p.Ala13Val](/variant/rint1-p-ala13val).

### 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 700586). 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.*