# NM_002439.5(MSH3):c.2294C>G (p.Pro765Arg)

https://sugi.bio/variant/msh3-p-pro765arg

## Summary

**MSH3 p.Pro765Arg (c.2294C>G)** is classified **Uncertain significance** in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-27). AlphaMissense: likely pathogenic (0.727); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1397708022 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MSH3 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 | [MSH3](https://sugi.bio/atlas/gene/MSH3/) |
| Protein change (HGVS p.) | p.Pro765Arg |
| Coding change (HGVS c.) | c.2294C>G |
| MANE Select transcript | [NM_002439](https://www.ncbi.nlm.nih.gov/nuccore/NM_002439) |
| dbSNP | [rs1397708022](https://www.ncbi.nlm.nih.gov/snp/rs1397708022/) |
| Variant type | single nucleotide variant |
| Location | chr5:80775734-80775734 (GRCh38) |
| ClinVar | [VCV946741](https://www.ncbi.nlm.nih.gov/clinvar/variation/946741/) |

**All HGVS expressions:** `NC_000005.10:g.80775734C>G`, `NC_000005.9:g.80071553C>G`, `NG_016607.2:g.126260C>G`, `NM_002439.5:c.2294C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.727)
- REVEL 0.713 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.532 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.604, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.0**. 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.*
- Regional missense constraint: **o/e 1.08** across the covering region of the MANE Select transcript (80,654,728–80,875,859), spanning 221,131 bp. Chi-square p 0.0024. 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>T, Δ0.33 acceptor loss), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**MSH3** population constraint: LOEUF 1.027, pLI 1.3015e-21, missense-Z -0.48793. *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):

- **familial adenomatous polyposis 4** — Definitive (AR)
- **Lynch syndrome** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.48, 61% of residues very-high.

**25 experimental structure(s)** (PDB): [3THW](https://www.rcsb.org/structure/3THW), [3THX](https://www.rcsb.org/structure/3THX), [3THY](https://www.rcsb.org/structure/3THY), [3THZ](https://www.rcsb.org/structure/3THZ), [8OLX](https://www.rcsb.org/structure/8OLX), [8OM5](https://www.rcsb.org/structure/8OM5).

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

*Describes the biological roles of MSH3 (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:** MSH3's established molecular role includes enzyme binding. In Reactome, MSH3 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MSH2**, **Defective Mismatch Repair Associated With MSH3**.

**Disease mechanism (Reactome):** MSH3 loss or alteration is curated in [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928), [Defective Mismatch Repair Associated With MSH3](https://reactome.org/content/detail/R-HSA-5632927).

### Pathways affected {#pathways}

MSH3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928) | curated |
| ⚕ [Defective Mismatch Repair Associated With MSH3](https://reactome.org/content/detail/R-HSA-5632927) | curated |
| [Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)](https://reactome.org/content/detail/R-HSA-5358606) | electronic |

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

**Molecular function:** enzyme binding.

**Biological process:** DNA repair, mismatch repair, maintenance of DNA repeat elements, negative regulation of DNA recombination.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-05-27 |

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

## Same-residue context {#hotspot}

Residue **765** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MSH3 p.Pro765fs](/variant/msh3-p-pro765fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH3 variant pages (same residue, condition, or type): [MSH3 p.Pro765Ser](/variant/msh3-p-pro765ser), [MSH3 p.Pro765Thr](/variant/msh3-p-pro765thr), [MSH3 p.Pro765fs](/variant/msh3-p-pro765fs), [MSH3 c.1341-2A>C](/variant/msh3-c-1341-minus-2a-c), [MSH3 c.1341-2A>G](/variant/msh3-c-1341-minus-2a-g), [MSH3 c.1568+1G>A](/variant/msh3-c-1568-plus-1g-a), [MSH3 c.1568+1G>C](/variant/msh3-c-1568-plus-1g-c), [MSH3 c.1653+1G>A](/variant/msh3-c-1653-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 946741). 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.*