Is MSH2 p.Pro616Ser (c.1846C>T) pathogenic?

MSH2 p.Pro616Ser (c.1846C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.2254); Very rare (popmax 0.00669%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Pro616Ser (c.1846C>T)?

MSH2 p.Pro616Ser (c.1846C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary breast ovarian cancer syndrome, Lynch syndrome (ClinVar).

How common is MSH2 p.Pro616Ser (c.1846C>T) in the general population?

MSH2 p.Pro616Ser (c.1846C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about MSH2 p.Pro616Ser (c.1846C>T)?

AlphaMissense predicts likely benign (score 0.2254) — an in-silico prediction, not a clinical call.

MSH2 p.Pro616Ser

c.1846C>T · rs587782627 · VCV142665

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.2254	likely benign
REVEL	0.731	pathogenic-leaning
SaProt	LLR -8.34	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	26.3	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 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,614,048 alleles · very rare exomes 4/1,461,816 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Admixed American	0.00167%	60,024

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.Pro616Ser
Coding: c.1846C>T
MANE Select: NM_000251
dbSNP: rs587782627
Type: single nucleotide variant
Location: chr2:47475111 (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 colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome Lynch syndrome hereditary neoplastic syndrome

Similar variants

MSH2 p.Pro616= Benign/Likely benign ★★ same residue
MSH2 p.Pro616Ala Uncertain significance ★ ⚠ same residue
MSH2 p.Pro616Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro616His Uncertain significance ★ ⚠ 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 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-pro616ser (accessed [today's date]).

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