# NM_005732.4(RAD50):c.1294A>G (p.Ile432Val)

https://sugi.bio/variant/rad50-p-ile432val

## Summary

**RAD50 p.Ile432Val (c.1294A>G)** is classified **Uncertain significance** in RAD50 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-09). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00134%, afr); Associated with Nijmegen breakage syndrome-like disorder.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs587782322 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the RAD50 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Nijmegen breakage syndrome-like disorder.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017184/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAD50](https://sugi.bio/atlas/gene/RAD50/) |
| Protein change (HGVS p.) | p.Ile432Val |
| Coding change (HGVS c.) | c.1294A>G |
| MANE Select transcript | [NM_005732](https://www.ncbi.nlm.nih.gov/nuccore/NM_005732) |
| dbSNP | [rs587782322](https://www.ncbi.nlm.nih.gov/snp/rs587782322/) |
| Variant type | single nucleotide variant |
| Location | chr5:132589679-132589679 (GRCh38) |
| ClinVar | [VCV408409](https://www.ncbi.nlm.nih.gov/clinvar/variation/408409/) |

**All HGVS expressions:** `LRG_312:g.37703A>G`, `LRG_312t1:c.1294A>G`, `NC_000005.10:g.132589679A>G`, `NC_000005.9:g.131925371A>G`, `NG_021151.2:g.37703A>G`, `NM_005732.4:c.1294A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0798)
- REVEL 0.089 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.536 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.038, GERP 4.01, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.6**. 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 0.92** across the covering region of the MANE Select transcript (132,557,325–132,595,607), spanning 38,282 bp. Chi-square p 0.02. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.26**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.26**.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/74,828 in the highest group · 4/1,610,978 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,828 |
| South Asian | 0.00111% | 90,458 |
| European (non-Finnish) | 0.00017% | 589,195 |

*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}

**RAD50** population constraint: LOEUF 0.889, pLI 1.1799e-33, missense-Z 2.2921; ClinGen dosage — haploinsufficiency 1/3, 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** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.83, 14% of residues very-high.

**6 experimental structure(s)** (PDB): [5GOX](https://www.rcsb.org/structure/5GOX), [9Q9H](https://www.rcsb.org/structure/9Q9H), [9Q9I](https://www.rcsb.org/structure/9Q9I), [9Q9J](https://www.rcsb.org/structure/9Q9J), [9Q9K](https://www.rcsb.org/structure/9Q9K), [9Q9M](https://www.rcsb.org/structure/9Q9M).

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

*Describes the biological roles of RAD50 (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:** RAD50's established molecular role includes DNA binding. In Reactome, RAD50 is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** RAD50 loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

RAD50 participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through MMEJ (alt-NHEJ)](https://reactome.org/content/detail/R-HSA-5685939) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | 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 |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [Sensing of DNA Double Strand Breaks](https://reactome.org/content/detail/R-HSA-5693548) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Molecular function:** DNA binding, ATP hydrolysis activity, protein-macromolecule adaptor activity, identical protein binding, protein serine/threonine kinase activator activity.

**Biological process:** regulation of mitotic recombination, double-strand break repair via homologous recombination, DNA double-strand break processing, DNA repair, double-strand break repair, DNA recombination.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-09.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-09 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-07 |

## Associated conditions {#conditions}

[Nijmegen breakage syndrome-like disorder](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome-like-disorder/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Nijmegen breakage syndrome-like disorder, Hereditary cancer-predisposing syndrome, MICROCEPHALY AND SPONTANEOUS CHROMOSOME INSTABILITY WITHOUT IMMUNODEFICIENCY, NBS-LIKE DISORDER, RAD50 DEFICIENCY, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **432** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RAD50 p.Ile432fs](/variant/rad50-p-ile432fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RAD50 variant pages (same residue, condition, or type): [RAD50 p.Ile432Leu](/variant/rad50-p-ile432leu), [RAD50 p.Ile432fs](/variant/rad50-p-ile432fs), [RAD50 c.1051+1G>A](/variant/rad50-c-1051-plus-1g-a), [RAD50 c.1052-1G>A](/variant/rad50-c-1052-minus-1g-a), [RAD50 c.1052-1G>T](/variant/rad50-c-1052-minus-1g-t), [RAD50 c.1052-2A>C](/variant/rad50-c-1052-minus-2a-c), [RAD50 c.1245+1G>A](/variant/rad50-c-1245-plus-1g-a), [RAD50 c.129+1G>A](/variant/rad50-c-129-plus-1g-a).

### 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 408409). 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.*