Is PMS2 p.Met1Arg (c.2T>G) pathogenic?

PMS2 p.Met1Arg (c.2T>G) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-04-28). Very rare (popmax 0.0011%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Met1Arg (c.2T>G)?

PMS2 p.Met1Arg (c.2T>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Met1Arg (c.2T>G) in the general population?

PMS2 p.Met1Arg (c.2T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

PMS2 p.Met1Arg

c.2T>G · rs587780059 · VCV231873

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.56	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Overall
CADD	25.2	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 · 1/91,022 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.Met1Arg
Coding: c.2T>G
MANE Select: NM_000535
dbSNP: rs587780059
Type: single nucleotide variant
Location: chr7:6009018 (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.Met1Val Likely pathogenic ★★★ same residue
PMS2 p.Met1Ile Pathogenic ★★ same residue
PMS2 p.Met1Leu Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Met1Lys Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Met1Thr Pathogenic ★★ same residue
PMS2 p.Met1fs Pathogenic ★ 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-met1arg (accessed [today's date]).

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