Is PMS2 p.Ser46Ile (c.137G>T) pathogenic?

PMS2 p.Ser46Ile (c.137G>T) is classified Likely pathogenic in PMS2 (ClinVar, Expert panel, 54 submitters; last evaluated 2019-06-21). AlphaMissense: likely pathogenic (0.9536); Ultra-rare (popmax 0.0353%, nfe); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Ser46Ile (c.137G>T)?

PMS2 p.Ser46Ile (c.137G>T) is associated with Lynch syndrome, endometrial carcinoma, Lynch syndrome 1 (ClinVar).

How common is PMS2 p.Ser46Ile (c.137G>T) in the general population?

PMS2 p.Ser46Ile (c.137G>T) is ultra-rare (popmax 0.0353%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about PMS2 p.Ser46Ile (c.137G>T)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

PMS2 p.Ser46Ile

c.137G>T · rs121434629 · VCV9245

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 54 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0353%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic ✓ concordant with ClinVar
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -17.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	29.8	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 0.0353% European (non-Finnish) · 416/1,179,868 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.0282% 454/1,610,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0353%	2,836
Remaining individualsnot grpmax-eligible	0.0337%	2,966
Admixed American	0.025%	3,999
African / African-American	0.00267%	37,430

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.Ser46Ile
Coding: c.137G>T
MANE Select: NM_000535
dbSNP: rs121434629
Type: single nucleotide variant
Location: chr7:6005918 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 46: a UniProt-annotated variant site (in mmrcs4 and lynch4; strongly decreased dna mismatch repair activity; no effect on protein abundance; no effect on subcellular localization); a UniProt-annotated variant site (in lynch4; strongly decreased dna mismatch repair activity); an α-helix

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: endometrial carcinoma Lynch syndrome 1 mismatch repair cancer syndrome 1 dilated cardiomyopathy 1G hypertrophic cardiomyopathy 9 Lynch syndrome 4 hereditary neoplastic syndrome pituitary adenocarcinoma mismatch repair cancer syndrome 4

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Ser46Asn Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Ser46Arg Uncertain significance ★ ⚠ same residue
PMS2 p.Ser46= Likely benign ★ same residue
PMS2 p.Ser46fs Pathogenic ★★ same residue
PMS2 p.Ser46Gly Uncertain significance ★ ⚠ 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-ser46ile (accessed [today's date]).

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