Is PMS2 p.Thr147Pro (c.439A>C) pathogenic?

PMS2 p.Thr147Pro (c.439A>C) is classified Uncertain significance in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: likely benign (0.2833); No allele count reported in gnomAD v4.1 (AN 1,611,044); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Thr147Pro (c.439A>C)?

PMS2 p.Thr147Pro (c.439A>C) is associated with Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Thr147Pro (c.439A>C) in the general population?

PMS2 p.Thr147Pro (c.439A>C) is no allele count reported in gnomAD v4.1 (AN 1,611,044) (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.Thr147Pro (c.439A>C)?

AlphaMissense predicts likely benign (score 0.2833) — an in-silico prediction, not a clinical call.

PMS2 p.Thr147Pro

c.439A>C · rs1583403496 · VCV802298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2833 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,044)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.2833	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -13.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	phastCons 0.27
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	20.4	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

No allele count reported in gnomAD v4.1 (AN 1,611,044). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PMS2
Protein: p.Thr147Pro
Coding: c.439A>C
MANE Select: NM_000535
dbSNP: rs1583403496
Type: single nucleotide variant
Location: chr7:6002551 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 147: a β-strand

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Thr147= Benign ★ same residue
PMS2 p.Thr147Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Thr147Ile Uncertain significance ★★ ⚠ same residue
PMS2 p.Thr147Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Thr147Ser Uncertain significance ★ ⚠ 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

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-thr147pro (accessed [today's date]).

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