# NM_130384.3(ATRIP):c.1186C>T (p.Arg396Cys)

https://sugi.bio/variant/atrip-p-arg396cys

## Summary

**ATRIP p.Arg396Cys (c.1186C>T)** is classified **Conflicting classifications of pathogenicity** in ATRIP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-17). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0627%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs373330865 · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0627%, afr)

## For patients & families {#patients}

This is a change in the ATRIP 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 | [ATRIP](https://sugi.bio/atlas/gene/ATRIP/) |
| Protein change (HGVS p.) | p.Arg396Cys |
| Coding change (HGVS c.) | c.1186C>T |
| MANE Select transcript | [NM_130384](https://www.ncbi.nlm.nih.gov/nuccore/NM_130384) |
| dbSNP | [rs373330865](https://www.ncbi.nlm.nih.gov/snp/rs373330865/) |
| Variant type | single nucleotide variant |
| Location | chr3:48460240-48460240 (GRCh38) |
| ClinVar | [VCV2187395](https://www.ncbi.nlm.nih.gov/clinvar/variation/2187395/) |

**All HGVS expressions:** `NC_000003.11:g.48501639C>T`, `NC_000003.12:g.48460240C>T`, `NG_041782.1:g.18531C>T`, `NM_001271022.2:c.805C>T`, `NM_001271023.2:c.907C>T`, `NM_032166.4:c.1186C>T`, `NM_130384.1:c.1186C>T`, `NM_130384.3:c.1186C>T`, `NR_153405.1:n.1253C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0661)
- REVEL 0.024 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.116 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.286, GERP -3.57 — weakly conserved position
- CADD: **PHRED 8.649**. 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 0.95** across the covering region of the MANE Select transcript (48,446,846–48,465,551), spanning 18,705 bp. Chi-square p 0.089. 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, Δ0.20 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): grpmax **0.0627%** (afr) · FAF95 0.0484% · FAF99 0.0433% · 47/74,930 in the highest group · 68/1,614,044 alleles overall — ultra-rare (popmax 0.0627%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0627% | 1,594 |
| Admixed American | 0.00833% | 11,999 |
| European (non-Finnish) | 0.00136% | 73,752 |

*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}

**ATRIP** population constraint: LOEUF 0.707, pLI 1.4374e-06, missense-Z 0.4195. *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** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.10, 35% of residues very-high.

**24 experimental structure(s)** (PDB): [4IGK](https://www.rcsb.org/structure/4IGK), [4NB3](https://www.rcsb.org/structure/4NB3), [5YZ0](https://www.rcsb.org/structure/5YZ0), [7XV4](https://www.rcsb.org/structure/7XV4), [13DE](https://www.rcsb.org/structure/13DE), [23EW](https://www.rcsb.org/structure/23EW).

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

*Describes the biological roles of ATRIP (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.*

**How this variant is thought to act:** ATRIP's established molecular role includes K63-linked polyubiquitin modification-dependent protein binding. In Reactome, ATRIP is annotated in disease pathway(s) including **Impaired BRCA2 binding to RAD51**.

**Disease mechanism (Reactome):** ATRIP loss or alteration is curated in [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570).

### Pathways affected {#pathways}

ATRIP participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [Activation of ATR in response to replication stress](https://reactome.org/content/detail/R-HSA-176187) | curated |
| [Fanconi Anemia Pathway](https://reactome.org/content/detail/R-HSA-6783310) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |

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

**Molecular function:** K63-linked polyubiquitin modification-dependent protein binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-17.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-17 |

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

## Similar variants {#similar}

Related ATRIP variant pages (same residue, condition, or type): [ATRIP p.Arg396His](/variant/atrip-p-arg396his), [ATRIP p.Arg396Ser](/variant/atrip-p-arg396ser), [TREX1 p.Arg114His](/variant/trex1-p-arg114his), [TREX1 p.Arg164Ter](/variant/trex1-p-arg164ter), [TREX1 p.Asp18Asn](/variant/trex1-p-asp18asn), [TREX1 p.Asp200His](/variant/trex1-p-asp200his), [TREX1 p.Gln135Ter](/variant/trex1-p-gln135ter), [ATRIP p.Ala119Thr](/variant/atrip-p-ala119thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2187395). 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.*