Is PMS2 p.Arg199Cys (c.595C>T) pathogenic?

PMS2 p.Arg199Cys (c.595C>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.2308); Ultra-rare (popmax 0.0317%, amr); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Arg199Cys (c.595C>T)?

PMS2 p.Arg199Cys (c.595C>T) is associated with Lynch syndrome 4, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg199Cys (c.595C>T) in the general population?

PMS2 p.Arg199Cys (c.595C>T) is ultra-rare (popmax 0.0317%, 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.Arg199Cys (c.595C>T)?

AlphaMissense predicts likely benign (score 0.2308) — an in-silico prediction, not a clinical call.

PMS2 p.Arg199Cys

c.595C>T · rs372297364 · VCV187514

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.2308 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.2308	likely benign
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -13.29	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	33.0	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 0.0317% Admixed American · 19/59,950 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00304% 49/1,613,616 alleles · ultra-rare exomes 31/1,461,608 · genomes 18/152,008 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,155
South Asian	0.0154%	6,506
Remaining individualsnot grpmax-eligible	0.0112%	8,922
African / African-American	0.00401%	24,949
East Asian	0.00223%	44,876
European (non-Finnish)	0.000424%	235,975

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.Arg199Cys
Coding: c.595C>T
MANE Select: NM_000535
dbSNP: rs372297364
Type: single nucleotide variant
Location: chr7:5999218 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 199: 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

Also linked: Lynch syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 4

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Arg199His Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg199Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg199Pro Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg199= Benign/Likely benign ★★ same residue
PMS2 p.Arg199Ser Uncertain significance ★ ⚠ same residue
PMS2 p.Arg199_Val200insTer Pathogenic ★★ same residue
PMS2 p.Arg199fs Pathogenic ★ 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-arg199cys (accessed [today's date]).

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