Is PMS2 p.Ile227= (c.681C>A) pathogenic?

PMS2 p.Ile227= (c.681C>A) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-05-18). Very rare (popmax 0.000254%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ile227= (c.681C>A) in the general population?

PMS2 p.Ile227= (c.681C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

PMS2 p.Ile227=

Q: What condition is associated with PMS2 p.Ile227= (c.681C>A)?

PMS2 p.Ile227= (c.681C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.681C>A · rs188813057 · VCV184464

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.54	donor loss, 24 bp away · masked 0 · deltas
Pangolin	Δ0.48	loss · gain 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -1.9
Overall
CADD	0.511	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,948 alleles · very rare exomes 2/1,461,872 · genomes 1/152,076 · 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.Ile227=
Coding: c.681C>A
MANE Select: NM_000535
dbSNP: rs188813057
Type: single nucleotide variant
Location: chr7:5999132 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 227: an α-helix

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 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Ile227Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile227Met Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile227Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile227Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile227Val Uncertain significance ★★ ⚠ same residue
PMS2 p.Ile227Asn Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
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-ile227 (accessed [today's date]).

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