Is MSH2 p.Pro616Arg (c.1847C>G) pathogenic?

MSH2 p.Pro616Arg (c.1847C>G) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-07-17). AlphaMissense: ambiguous (0.4126); Ultra-rare (popmax 0.0329%, mid); Associated with hereditary nonpolyposis colon cancer.

What condition is associated with MSH2 p.Pro616Arg (c.1847C>G)?

MSH2 p.Pro616Arg (c.1847C>G) is associated with hereditary nonpolyposis colon cancer, colon carcinoma, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Pro616Arg (c.1847C>G) in the general population?

MSH2 p.Pro616Arg (c.1847C>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MSH2 p.Pro616Arg (c.1847C>G)?

AlphaMissense predicts ambiguous (score 0.4126) — an in-silico prediction, not a clinical call.

MSH2 p.Pro616Arg

c.1847C>G · rs587779965 · VCV127636

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

ambiguous

0.4126 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary nonpolyposis colon cancer

Computational evidence

Protein change
AlphaMissense	0.4126	ambiguous
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	26.9	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00322% 52/1,613,962 alleles · ultra-rare exomes 48/1,461,822 · genomes 4/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.0283%	3,530
European (non-Finnish)	0.00271%	36,875
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Pro616Arg
Coding: c.1847C>G
MANE Select: NM_000251
dbSNP: rs587779965
Type: single nucleotide variant
Location: chr2:47475112 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 616: the 'interaction with exo1' region; a β-strand

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

Disease context

hereditary nonpolyposis colon cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colon carcinoma Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Pro616= Benign/Likely benign ★★ same residue
MSH2 p.Pro616His Uncertain significance ★ ⚠ same residue
MSH2 p.Pro616Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro616Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro616Leu Likely benign ★ ⚠ same residue
MSH2 p.Pro616fs Pathogenic ★★ same residue
MSH2 p.Pro616Ala Uncertain significance ★ ⚠ 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-pro616arg (accessed [today's date]).

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