Is PMS2 p.Glu2Ter (c.4G>T) pathogenic?

PMS2 p.Glu2Ter (c.4G>T) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). Very rare (popmax 8.48e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Glu2Ter (c.4G>T)?

PMS2 p.Glu2Ter (c.4G>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Glu2Ter (c.4G>T) in the general population?

PMS2 p.Glu2Ter (c.4G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

PMS2 p.Glu2Ter

c.4G>T · rs1554309080 · VCV1458829

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 7.2	phastCons 1
Overall
CADD	57.0	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 8.48e-05% European (non-Finnish) · 1/1,179,846 alleles

Overall 6.85e-05% 1/1,460,252 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.Glu2Ter
Coding: c.4G>T
MANE Select: NM_000535
dbSNP: rs1554309080
Type: single nucleotide variant
Location: chr7:6009016 (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

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Glu2Gln Uncertain significance ★★ ⚠ same residue
PMS2 p.Glu2Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Glu2= Benign/Likely benign ★★ same residue
PMS2 p.Glu2Asp Uncertain significance ★ ⚠ same residue
PMS2 p.Glu2Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Glu2_Arg3= Likely benign ★ 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-glu2ter (accessed [today's date]).

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