Is PMS2 p.Ser7Ter (c.20C>A) pathogenic?

PMS2 p.Ser7Ter (c.20C>A) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-01). Very rare (popmax 0.0011%, sas); Associated with PMS2-related disorder.

What condition is associated with PMS2 p.Ser7Ter (c.20C>A)?

PMS2 p.Ser7Ter (c.20C>A) is associated with PMS2-related disorder, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser7Ter (c.20C>A) in the general population?

PMS2 p.Ser7Ter (c.20C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

PMS2 p.Ser7Ter

c.20C>A · rs587780048 · VCV2674248

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

PMS2-related disorder

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 1 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5
Overall
CADD	36.0	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 0.0011% South Asian · 1/91,026 alleles

Overall 6.85e-05% 1/1,460,306 alleles · very rare

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.Ser7Ter
Coding: c.20C>A
MANE Select: NM_000535
dbSNP: rs587780048
Type: single nucleotide variant
Location: chr7:6009000 (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

PMS2-related disorder

Also linked: Lynch syndrome 4

Similar variants

PMS2 p.Ser7Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser7= Benign/Likely benign ★★ same residue
PMS2 p.Ser7Trp Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser7Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.705+1G>T 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-ser7ter (accessed [today's date]).

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