Is PMS2 p.Arg628Ter (c.1882C>T) pathogenic?

PMS2 p.Arg628Ter (c.1882C>T) is classified Pathogenic in PMS2 (ClinVar, Expert panel, 23 submitters; last evaluated 2013-09-05). Very rare (popmax 0.00167%, amr); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Arg628Ter (c.1882C>T)?

PMS2 p.Arg628Ter (c.1882C>T) is associated with Lynch syndrome, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg628Ter (c.1882C>T) in the general population?

PMS2 p.Arg628Ter (c.1882C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Arg628Ter

c.1882C>T · rs63750451 · VCV9242

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 23 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Lynch syndrome

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 6.7	phastCons 1
Overall
CADD	38.0	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 0.00167% Admixed American · 1/59,968 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,798 alleles · very rare exomes 12/1,461,858 · genomes 0/151,940 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,968
European (non-Finnish)	0.000932%	107,269

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.Arg628Ter
Coding: c.1882C>T
MANE Select: NM_000535
dbSNP: rs63750451
Type: single nucleotide variant
Location: chr7:5986883 (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

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

Also linked: Lynch syndrome 4 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.Arg628Pro Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg628Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Arg628Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Arg628= Likely benign ★ same residue
PMS2 p.Arg628_Ile629insTer Pathogenic ★★ 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

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-arg628ter (accessed [today's date]).

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