Is PMS2 p.Cys216= (c.648C>T) pathogenic?

PMS2 p.Cys216= (c.648C>T) is classified Likely benign in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-29). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Cys216= (c.648C>T)?

PMS2 p.Cys216= (c.648C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Cys216= (c.648C>T) in the general population?

PMS2 p.Cys216= (c.648C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PMS2 p.Cys216=

c.648C>T · rs762387250 · VCV486056

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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	Δ0.72	donor gain · deltas
Pangolin	Δ0.61	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3	phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.2e-05% 1/1,614,092 alleles · very rare exomes 1/1,461,876 · genomes 0/152,216 · 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.Cys216=
Coding: c.648C>T
MANE Select: NM_000535
dbSNP: rs762387250
Type: single nucleotide variant
Location: chr7:5999165 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 216: a β-strand

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

Similar variants

PMS2 p.Cys216Arg Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys216Trp Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys216Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Cys216Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.Cys216fs Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Cys216Ter Pathogenic ★ same residue
PMS2 p.Cys216Gly Uncertain significance ★ ⚠ same residue
PMS2 c.163+2T>C 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-cys216 (accessed [today's date]).

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