Is PMS2 p.Gln275= (c.825A>G) pathogenic?

PMS2 p.Gln275= (c.825A>G) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-06-02). Very rare (popmax 0.00446%, eas); Associated with hereditary nonpolyposis colon cancer.

What condition is associated with PMS2 p.Gln275= (c.825A>G)?

PMS2 p.Gln275= (c.825A>G) is associated with hereditary nonpolyposis colon cancer, gastric cancer, Lynch syndrome (ClinVar).

How common is PMS2 p.Gln275= (c.825A>G) in the general population?

PMS2 p.Gln275= (c.825A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

PMS2 p.Gln275=

c.825A>G · rs876659736 · VCV232390

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary nonpolyposis colon cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.79	acceptor gain · deltas
Pangolin	Δ0.72	gain · loss 0.17 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.53
Overall
CADD	19.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000205% 3/1,460,892 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
African / African-American	0.00133%	75,024

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: PMS2
Protein: p.Gln275=
Coding: c.825A>G
MANE Select: NM_000535
dbSNP: rs876659736
Type: single nucleotide variant
Location: chr7:5995612 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

Full PMS2 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: gastric cancer Lynch syndrome mismatch repair cancer syndrome 1 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Gln275Ter Pathogenic ★★ same residue
PMS2 p.Gln275Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Gln275Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Gln275His Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Gln275Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Gln275Pro Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C 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/pms2-p-gln275 (accessed [today's date]).

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