Is PMS2 p.Ser220Ile (c.659G>T) pathogenic?

PMS2 p.Ser220Ile (c.659G>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1137); Ultra-rare (popmax 0.0121%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ser220Ile (c.659G>T)?

PMS2 p.Ser220Ile (c.659G>T) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser220Ile (c.659G>T) in the general population?

PMS2 p.Ser220Ile (c.659G>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Ser220Ile (c.659G>T)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

PMS2 p.Ser220Ile

c.659G>T · rs769967916 · VCV928304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,092 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000743% 12/1,613,990 alleles · ultra-rare exomes 10/1,461,888 · genomes 2/152,102 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Ser220Ile
Coding: c.659G>T
MANE Select: NM_000535
dbSNP: rs769967916
Type: single nucleotide variant
Location: chr7:5999154 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4

Similar variants

PMS2 p.Ser220Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser220Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser220Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser220= Benign/Likely benign ★★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>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-ser220ile (accessed [today's date]).

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