Is PMS2 p.Pro395= (c.1185C>T) pathogenic?

PMS2 p.Pro395= (c.1185C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-30). Very rare (popmax 0.00017%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Pro395= (c.1185C>T) in the general population?

PMS2 p.Pro395= (c.1185C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

PMS2 p.Pro395=

Q: What condition is associated with PMS2 p.Pro395= (c.1185C>T)?

PMS2 p.Pro395= (c.1185C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, breast cancer, Lynch syndrome 4 (ClinVar).

c.1185C>T · rs1562636721 · VCV560795

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5
Overall
CADD	0.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,586 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,956 alleles · very rare exomes 2/1,458,896 · genomes 0/152,060 · 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.Pro395=
Coding: c.1185C>T
MANE Select: NM_000535
dbSNP: rs1562636721
Type: single nucleotide variant
Location: chr7:5987580 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 395: the 'disordered' region

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer Lynch syndrome 4

Similar variants

PMS2 p.Pro395Arg Uncertain significance ★ ⚠ same residue
PMS2 p.Pro395Ala Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro395His Uncertain significance ★ ⚠ same residue
PMS2 p.Pro395Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Pro395Ser Conflicting classifications of pathogenicity ★ ⚠ 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-pro395 (accessed [today's date]).

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