Is PMS2 p.Cys276= (c.828C>T) pathogenic?

PMS2 p.Cys276= (c.828C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-09). Very rare (popmax 0.00133%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Cys276= (c.828C>T)?

PMS2 p.Cys276= (c.828C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Cys276= (c.828C>T) in the general population?

PMS2 p.Cys276= (c.828C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

PMS2 p.Cys276=

c.828C>T · rs757324104 · VCV230650

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.5	phastCons 0.004
Overall
CADD	0.926	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,016 alleles

Overall 6.2e-05% 1/1,613,276 alleles · very rare exomes 1/1,461,004 · genomes 0/152,272 · 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.Cys276=
Coding: c.828C>T
MANE Select: NM_000535
dbSNP: rs757324104
Type: single nucleotide variant
Location: chr7:5995609 (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 nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Cys276Ter Pathogenic ★★ same residue
PMS2 p.Cys276Arg Uncertain significance ★★ same residue
PMS2 p.Cys276Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys276Gly Uncertain significance ★ ⚠ same residue
PMS2 p.Cys276Phe Uncertain significance ★ ⚠ same residue
PMS2 p.Cys276Ser Uncertain significance ★ ⚠ same residue
PMS2 p.Cys276Trp 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-cys276 (accessed [today's date]).

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