Is MSH2 p.Pro622Ser (c.1864C>T) pathogenic?

MSH2 p.Pro622Ser (c.1864C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.9669); Very rare (popmax 8.47e-05%, nfe); Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Pro622Ser (c.1864C>T)?

MSH2 p.Pro622Ser (c.1864C>T) is associated with Lynch syndrome 1, Lynch syndrome (ClinVar).

How common is MSH2 p.Pro622Ser (c.1864C>T) in the general population?

MSH2 p.Pro622Ser (c.1864C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH2 p.Pro622Ser (c.1864C>T)?

AlphaMissense predicts likely pathogenic (score 0.9669) — an in-silico prediction, not a clinical call.

MSH2 p.Pro622Ser

c.1864C>T · rs63750280 · VCV3073881

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9669	likely pathogenic
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -13.78	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 7.7	GERP 1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	26.7	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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,032 alleles · very rare exomes 1/1,461,876 · genomes 0/152,156 · joint denominator

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.Pro622Ser
Coding: c.1864C>T
MANE Select: NM_000251
dbSNP: rs63750280
Type: single nucleotide variant
Location: chr2:47475129 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 622: the 'interaction with exo1' region; a UniProt-annotated variant site (in lynch1; decreased mismatch repair activity; confers multiple biochemical defects)

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

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Pro622Leu Pathogenic ★★★ same residue
MSH2 p.Pro622Arg Pathogenic/Likely pathogenic ★★ same residue
MSH2 p.Pro622Gln Likely pathogenic ★★ same residue
MSH2 p.Pro622Thr Pathogenic/Likely pathogenic ★★ same residue
MSH2 p.Pro622fs Pathogenic ★★ same residue
MSH2 p.Pro622Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro622= Likely benign ★ 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-pro622ser (accessed [today's date]).

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