Is MSH2 p.Gln409= (c.1227G>A) pathogenic?

MSH2 p.Gln409= (c.1227G>A) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-18). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Gln409= (c.1227G>A)?

MSH2 p.Gln409= (c.1227G>A) is associated with hereditary neoplastic syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Gln409= (c.1227G>A) in the general population?

MSH2 p.Gln409= (c.1227G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MSH2 p.Gln409=

c.1227G>A · VCV3722505

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

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

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.034	moderately benign-leaning
Splicing
SpliceAI	Δ0.82	donor gain · deltas
Pangolin	Δ0.74	gain · loss 0.37 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 1.5, phastCons 1
Overall
CADD	20.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,986 alleles

Overall 6.2e-05% 1/1,614,026 alleles · very rare exomes 1/1,461,802 · genomes 0/152,224 · 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.Gln409=
Coding: c.1227G>A
MANE Select: NM_000251
Type: single nucleotide variant
Location: chr2:47429892 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 409: an α-helix

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

Disease context

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

Also linked: Lynch syndrome 1

Similar variants

MSH2 p.Gln409Ter Pathogenic ★★ same residue
MSH2 p.Gln409Arg Uncertain significance ★★ ⚠ same residue
MSH2 p.Gln409Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Gln409His Uncertain significance ★ ⚠ same residue
MSH2 p.Gln409fs Pathogenic ★★★ same residue
MSH2 p.Gln409Lys Uncertain significance ★★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely 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-gln409 (accessed [today's date]).

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