# NM_021930.6(RINT1):c.1335T>C (p.Phe445=)

https://sugi.bio/variant/rint1-p-phe445

## Summary

**RINT1 p.Phe445= (c.1335T>C)** is classified **Conflicting classifications of pathogenicity** in RINT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-03). Very rare (popmax 0.00683%, sas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs770595233 · 2 submitters · very rare (popmax 0.00683%, sas)

## For patients & families {#patients}

This is a change in the RINT1 gene that is of uncertain or conflicting significance (submitters disagree on it), 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.Phe445= |
| Coding change (HGVS c.) | c.1335T>C |
| MANE Select transcript | [NM_021930](https://www.ncbi.nlm.nih.gov/nuccore/NM_021930) |
| dbSNP | [rs770595233](https://www.ncbi.nlm.nih.gov/snp/rs770595233/) |
| Variant type | single nucleotide variant |
| Location | chr7:105551571-105551571 (GRCh38) |
| ClinVar | [VCV416375](https://www.ncbi.nlm.nih.gov/clinvar/variation/416375/) |

**All HGVS expressions:** `NC_000007.13:g.105192018T>C`, `NC_000007.14:g.105551571T>C`, `NG_051951.1:g.24491T>C`, `NM_001346599.2:c.1101T>C`, `NM_001346600.2:c.312T>C`, `NM_001346601.2:c.411T>C`, `NM_001346603.2:c.312T>C`, `NM_021930.6:c.1335T>C`, `NR_144478.2:n.1450T>C`

## 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 2.846, GERP 3.17, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.0**. 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 (T>A, Δ0.98 acceptor gain), 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 **0.00683%** (sas) · FAF95 0.00295% · FAF99 0.00201% · 6/87,908 in the highest group · 27/1,595,740 alleles overall — very rare (popmax 0.00683%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00811% | 12,334 |
| South Asian (grpmax) | 0.00683% | 14,651 |
| European (non-Finnish) | 0.00137% | 73,199 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **445** lies in the rint1/tip20 domain.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-03.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-03 |

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

## Similar variants {#similar}

Related RINT1 variant pages (same residue, condition, or type): [RINT1 p.Phe445Leu](/variant/rint1-p-phe445leu), [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 2026-10-14); 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 416375). 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.*