Is PMS2 p.Arg3Leu (c.8G>T) pathogenic?

PMS2 p.Arg3Leu (c.8G>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.0789); Ultra-rare (popmax 0.0242%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Arg3Leu (c.8G>T) in the general population?

PMS2 p.Arg3Leu (c.8G>T) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Arg3Leu (c.8G>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

PMS2 p.Arg3Leu

Q: What condition is associated with PMS2 p.Arg3Leu (c.8G>T)?

PMS2 p.Arg3Leu (c.8G>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.8G>T · rs375507981 · VCV574206

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.5
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	0.814	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/91,022 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00164% 24/1,460,262 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,137
Admixed American	0.00167%	60,030
Remaining individualsnot grpmax-eligible	0.0016%	62,372

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.Arg3Leu
Coding: c.8G>T
MANE Select: NM_000535
dbSNP: rs375507981
Type: single nucleotide variant
Location: chr7:6009012 (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 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Arg3Ter Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Arg3Gln Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg3Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg3Pro Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg3= Benign/Likely benign ★★ 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-arg3leu (accessed [today's date]).

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