Is PMS2 p.Gly228= (c.684C>A) pathogenic?

PMS2 p.Gly228= (c.684C>A) is classified Likely benign in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-11). Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Gly228= (c.684C>A)?

PMS2 p.Gly228= (c.684C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Gly228= (c.684C>A) in the general population?

PMS2 p.Gly228= (c.684C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

PMS2 p.Gly228=

c.684C>A · rs371876208 · VCV1755775

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.52	phastCons 0.98
Overall
CADD	4.964	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,890 alleles

Overall 6.2e-05% 1/1,613,970 alleles · very rare exomes 0/1,461,882 · genomes 1/152,088 · 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: PMS2
Protein: p.Gly228=
Coding: c.684C>A
MANE Select: NM_000535
dbSNP: rs371876208
Type: single nucleotide variant
Location: chr7:5999129 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 228: an α-helix

Full PMS2 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

Similar variants

PMS2 p.Gly228Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Gly228Asp Uncertain significance ★ ⚠ same residue
PMS2 p.Gly228Cys Uncertain significance ★ ⚠ same residue
PMS2 p.Gly228Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+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/pms2-p-gly228 (accessed [today's date]).

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