Is PMS2 p.Pro246Arg (c.737C>G) pathogenic?

PMS2 p.Pro246Arg (c.737C>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1269); Very rare (popmax 0.00168%, amr); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Pro246Arg (c.737C>G)?

PMS2 p.Pro246Arg (c.737C>G) is associated with Lynch syndrome 4, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Pro246Arg (c.737C>G) in the general population?

PMS2 p.Pro246Arg (c.737C>G) is very rare (popmax 0.00168%, amr) (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.Pro246Arg (c.737C>G)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

PMS2 p.Pro246Arg

c.737C>G · rs1562670885 · VCV630020

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,370 alleles

Overall 0.000125% 2/1,604,698 alleles · very rare exomes 1/1,454,136 · genomes 1/150,562 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,370
African / African-American	0.00135%	74,116

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.Pro246Arg
Coding: c.737C>G
MANE Select: NM_000535
dbSNP: rs1562670885
Type: single nucleotide variant
Location: chr7:5997392 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 246: an α-helix

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

Also linked: Lynch syndrome hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Pro246His Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro246Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro246Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro246Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro246= Benign/Likely benign ★★ same residue
PMS2 p.Pro246fs Pathogenic ★★ same residue
PMS2 p.Pro246_Pro247delinsValValLys Uncertain significance ★ same residue
PMS2 c.1144+2T>A 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-pro246arg (accessed [today's date]).

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