# NM_021930.6(RINT1):c.1208A>T (p.Asp403Val)

https://sugi.bio/variant/rint1-p-asp403val

## Summary

**RINT1 p.Asp403Val (c.1208A>T)** is classified **Uncertain significance** in RINT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely pathogenic (0.977); Very rare (popmax 6.2e-05%).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs747055027 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the RINT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [RINT1](https://sugi.bio/atlas/gene/RINT1/) |
| Protein change (HGVS p.) | p.Asp403Val |
| Coding change (HGVS c.) | c.1208A>T |
| MANE Select transcript | [NM_021930](https://www.ncbi.nlm.nih.gov/nuccore/NM_021930) |
| dbSNP | [rs747055027](https://www.ncbi.nlm.nih.gov/snp/rs747055027/) |
| Variant type | single nucleotide variant |
| Location | chr7:105550361-105550361 (GRCh38) |
| ClinVar | [VCV1749220](https://www.ncbi.nlm.nih.gov/clinvar/variation/1749220/) |

**All HGVS expressions:** `NC_000007.13:g.105190808A>T`, `NC_000007.14:g.105550361A>T`, `NG_051951.1:g.23281A>T`, `NM_001346599.2:c.974A>T`, `NM_001346600.2:c.185A>T`, `NM_001346601.2:c.284A>T`, `NM_001346603.2:c.185A>T`, `NM_021930.6:c.1208A>T`, `NR_144478.2:n.1323A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.977)
- REVEL 0.587 (indeterminate)
- SaProt LLR -14.442 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.176, GERP 3.42, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in RINT1 (of 4,643 modeled).
- CADD: **PHRED 27.9**. 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 0.96** across the covering region of the MANE Select transcript (105,532,316–105,567,308), spanning 34,992 bp. Chi-square p 0.28. 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 (A>G, Δ0.67 donor 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): global (via dbSNP) **6.2e-05%** · 1/1,614,008 alleles overall — very rare (popmax 6.2e-05%).

*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 **403** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-03.

**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 | 2025-01-03 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **403** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RINT1 p.Asp403fs](/variant/rint1-p-asp403fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RINT1 variant pages (same residue, condition, or type): [RINT1 p.Asp403Asn](/variant/rint1-p-asp403asn), [RINT1 p.Asp403Glu](/variant/rint1-p-asp403glu), [RINT1 p.Asp403Gly](/variant/rint1-p-asp403gly), [RINT1 p.Asp403His](/variant/rint1-p-asp403his), [RINT1 p.Asp403Tyr](/variant/rint1-p-asp403tyr), [RINT1 p.Asp403=](/variant/rint1-p-asp403), [RINT1 p.Asp403fs](/variant/rint1-p-asp403fs), [RINT1 c.1107+1G>T](/variant/rint1-c-1107-plus-1g-t).

### 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 1749220). 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.*