Is PMS2 p.Glu489= (c.1467G>A) pathogenic?

PMS2 p.Glu489= (c.1467G>A) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0286%, nfe); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Glu489= (c.1467G>A)?

PMS2 p.Glu489= (c.1467G>A) is associated with Lynch syndrome 4, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Glu489= (c.1467G>A) in the general population?

PMS2 p.Glu489= (c.1467G>A) is ultra-rare (popmax 0.0286%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Glu489=

c.1467G>A · rs542522853 · VCV135938

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, nfe)

Conditions

Lynch syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.6
Overall
CADD	0.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0286% European (non-Finnish) · 338/1,180,054 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.0217% 350/1,614,078 alleles · ultra-rare exomes 329/1,461,884 · genomes 21/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0286%	3,491
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00534%	18,731
South Asian	0.0011%	91,092

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.Glu489=
Coding: c.1467G>A
MANE Select: NM_000535
dbSNP: rs542522853
Type: single nucleotide variant
Location: chr7:5987298 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 489: the 'disordered' region

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 4

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Glu489Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Glu489Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Glu489_Val490delinsAlaMet Uncertain significance ★ same residue
PMS2 p.Glu489Asp Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
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

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-glu489 (accessed [today's date]).

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