# NM_000251.3(MSH2):c.1243C>G (p.Pro415Ala)

https://sugi.bio/variant/msh2-p-pro415ala

## Summary

**MSH2 p.Pro415Ala (c.1243C>G)** is classified **Uncertain significance** in MSH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-09). AlphaMissense: likely benign (0.1408); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs35717997 · 3 submitters · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MSH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MSH2](https://sugi.bio/atlas/gene/MSH2/) |
| Protein change (HGVS p.) | p.Pro415Ala |
| Coding change (HGVS c.) | c.1243C>G |
| MANE Select transcript | [NM_000251](https://www.ncbi.nlm.nih.gov/nuccore/NM_000251) |
| dbSNP | [rs35717997](https://www.ncbi.nlm.nih.gov/snp/rs35717997/) |
| Variant type | single nucleotide variant |
| Location | chr2:47429908-47429908 (GRCh38) |
| ClinVar | [VCV486877](https://www.ncbi.nlm.nih.gov/clinvar/variation/486877/) |

**All HGVS expressions:** `LRG_218:g.31785C>G`, `NC_000002.11:g.47657047C>G`, `NC_000002.12:g.47429908C>G`, `NG_007110.2:g.31785C>G`, `NM_000251.3:c.1243C>G`, `NM_001258281.1:c.1045C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1408)
- REVEL 0.807 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.017 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.548, GERP 1.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. 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 1.30** across the covering region of the MANE Select transcript (47,403,192–47,482,946), spanning 79,754 bp. Chi-square p 4.9e-24. 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, Δ0.23 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: **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}

**MSH2** population constraint: LOEUF 0.672, pLI 4.5659e-06, missense-Z -2.8782; ClinGen dosage — haploinsufficiency 3/3, 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):

- **Lynch syndrome** — Definitive (AD)
- **mismatch repair cancer syndrome 1** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)

## Protein context {#protein}

Residue **415** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.60, 46% of residues very-high.

**30 experimental structure(s)** (PDB): [2O8B](https://www.rcsb.org/structure/2O8B), [2O8C](https://www.rcsb.org/structure/2O8C), [2O8D](https://www.rcsb.org/structure/2O8D), [2O8E](https://www.rcsb.org/structure/2O8E), [2O8F](https://www.rcsb.org/structure/2O8F), [3THW](https://www.rcsb.org/structure/3THW).

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

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

**Disease mechanism (Reactome):** MSH2 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), [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968).

### Pathways affected {#pathways}

MSH2 participates in **7 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 |
| ⚕ [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968) | curated |
| [Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)](https://reactome.org/content/detail/R-HSA-5358565) | curated |
| [Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)](https://reactome.org/content/detail/R-HSA-9968295) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | 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:** DNA binding, chromatin binding, enzyme activator activity, ATP-dependent activity, acting on DNA, guanine/thymine mispair binding, protein homodimerization activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-05-09.

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

**Submission history:** 3 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-03 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-09 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Hereditary nonpolyposis colorectal neoplasms, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **415** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MSH2 p.Pro415fs](/variant/msh2-p-pro415fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH2 variant pages (same residue, condition, or type): [MSH2 p.Pro415Arg](/variant/msh2-p-pro415arg), [MSH2 p.Pro415Leu](/variant/msh2-p-pro415leu), [MSH2 p.Pro415=](/variant/msh2-p-pro415), [MSH2 p.Pro415Ser](/variant/msh2-p-pro415ser), [MSH2 p.Pro415His](/variant/msh2-p-pro415his), [MSH2 p.Pro415fs](/variant/msh2-p-pro415fs), [MSH2 c.1076+1G>A](/variant/msh2-c-1076-plus-1g-a), [MSH2 c.1076+1G>T](/variant/msh2-c-1076-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 486877). 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.*