Is PMS2 p.Ser195= (c.585A>G) pathogenic?

PMS2 p.Ser195= (c.585A>G) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-30). Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ser195= (c.585A>G)?

PMS2 p.Ser195= (c.585A>G) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser195= (c.585A>G) in the general population?

PMS2 p.Ser195= (c.585A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

PMS2 p.Ser195=

c.585A>G · rs2536321183 · VCV1750108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.85	acceptor loss · deltas
Pangolin	Δ0.26	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 0.39	phastCons 0.1
Overall
CADD	17.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,998 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,110 alleles · very rare exomes 4/1,461,844 · genomes 0/152,266 · joint denominator

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.Ser195=
Coding: c.585A>G
MANE Select: NM_000535
dbSNP: rs2536321183
Type: single nucleotide variant
Location: chr7:5999228 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4

Similar variants

PMS2 p.Ser195Ter Pathogenic ★★ same residue
PMS2 p.Ser195Leu 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
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.705+1G>T 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-ser195 (accessed [today's date]).

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