Is MSH2 p.Arg39Pro (c.116G>C) pathogenic?

MSH2 p.Arg39Pro (c.116G>C) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9968); Very rare (popmax 8.49e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Arg39Pro (c.116G>C) in the general population?

MSH2 p.Arg39Pro (c.116G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Arg39Pro (c.116G>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

MSH2 p.Arg39Pro

Q: What condition is associated with MSH2 p.Arg39Pro (c.116G>C)?

MSH2 p.Arg39Pro (c.116G>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 1 (ClinVar).

c.116G>C · rs587782759 · VCV142842

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 4% in MSH2
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -17.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,182 alleles

Overall 0.000499% 8/1,604,180 alleles · very rare exomes 8/1,451,802 · genomes 0/152,378 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00805%	12,428
Finnishnot grpmax-eligible	0.00321%	31,137
European (non-Finnish)grpmax	8.49e-05%	1,177,182

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MSH2
Protein: p.Arg39Pro
Coding: c.116G>C
MANE Select: NM_000251
dbSNP: rs587782759
Type: single nucleotide variant
Location: chr2:47403307 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Arg39Trp Uncertain significance ★★ ⚠ same residue
MSH2 p.Arg39= Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Arg39Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Arg39Gly Uncertain significance ★ ⚠ same residue
MSH2 p.Arg39Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Arg39_Asp41del Uncertain significance ★★ same residue
MSH2 p.Arg39fs Pathogenic ★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/msh2-p-arg39pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown