Is PMS2 p.Cys276Arg (c.826T>C) pathogenic?

PMS2 p.Cys276Arg (c.826T>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-07). AlphaMissense: ambiguous (0.5604); Very rare (popmax 0.00223%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Cys276Arg (c.826T>C) in the general population?

PMS2 p.Cys276Arg (c.826T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PMS2 p.Cys276Arg (c.826T>C)?

AlphaMissense predicts ambiguous (score 0.5604) — an in-silico prediction, not a clinical call.

PMS2 p.Cys276Arg

Q: What condition is associated with PMS2 p.Cys276Arg (c.826T>C)?

PMS2 p.Cys276Arg (c.826T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.826T>C · rs1407229027 · VCV571426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.5604	ambiguous
REVEL	0.572	indeterminate
SaProt	LLR -12.33	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	19.35	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 0.00223% East Asian · 1/44,884 alleles

Overall 0.000124% 2/1,613,312 alleles · very rare exomes 2/1,461,000 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Finnishnot grpmax-eligible	0.00156%	64,034

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.Cys276Arg
Coding: c.826T>C
MANE Select: NM_000535
dbSNP: rs1407229027
Type: single nucleotide variant
Location: chr7:5995611 (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: hereditary neoplastic syndrome

Similar variants

PMS2 p.Cys276Ter Pathogenic ★★ same residue
PMS2 p.Cys276Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Cys276= Benign/Likely benign ★★ 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.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-cys276arg (accessed [today's date]).

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