Is PMS2 p.Arg563Ter (c.1687C>T) pathogenic?

PMS2 p.Arg563Ter (c.1687C>T) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-26). Very rare (popmax 0.00133%, afr); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Arg563Ter (c.1687C>T)?

PMS2 p.Arg563Ter (c.1687C>T) is associated with Lynch syndrome 4, colon carcinoma, Lynch syndrome (ClinVar).

How common is PMS2 p.Arg563Ter (c.1687C>T) in the general population?

PMS2 p.Arg563Ter (c.1687C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Arg563Ter

c.1687C>T · rs587778618 · VCV135067

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Lynch syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,872 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
South Asian	0.0011%	91,086
European (non-Finnish)	0.000254%	393,345

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.Arg563Ter
Coding: c.1687C>T
MANE Select: NM_000535
dbSNP: rs587778618
Type: single nucleotide variant
Location: chr7:5987078 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 563: a UniProt-annotated variant site (in lynch4; likely benign; normal dna mismatch repair activity)

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: colon carcinoma Lynch syndrome hereditary neoplastic syndrome hereditary nonpolyposis colon cancer mismatch repair cancer syndrome 4

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Arg563Leu Likely benign ★★★ same residue
PMS2 p.Arg563Pro Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg563= Benign/Likely benign ★★ same residue
PMS2 p.Arg563fs Pathogenic ★★ same residue
PMS2 p.Arg563Gln Conflicting classifications of pathogenicity ★ same residue
PMS2 p.Arg563Gly 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-arg563ter (accessed [today's date]).

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