Is PMS2 p.Ser7Trp (c.20C>G) pathogenic?

PMS2 p.Ser7Trp (c.20C>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-12). AlphaMissense: likely benign (0.1478); Very rare (popmax 0.00769%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ser7Trp (c.20C>G)?

PMS2 p.Ser7Trp (c.20C>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ser7Trp (c.20C>G) in the general population?

PMS2 p.Ser7Trp (c.20C>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about PMS2 p.Ser7Trp (c.20C>G)?

AlphaMissense predicts likely benign (score 0.1478) — an in-silico prediction, not a clinical call.

PMS2 p.Ser7Trp

c.20C>G · rs587780048 · VCV234058

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1478	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	13.38	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 0.00769% South Asian · 7/91,026 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000548% 8/1,460,306 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,004
Remaining individualsnot grpmax-eligible	0.0016%	62,382

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.Ser7Trp
Coding: c.20C>G
MANE Select: NM_000535
dbSNP: rs587780048
Type: single nucleotide variant
Location: chr7:6009000 (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 hereditary neoplastic syndrome

Similar variants

PMS2 p.Ser7Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser7= Benign/Likely benign ★★ same residue
PMS2 p.Ser7Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ser7Ter Pathogenic/Likely pathogenic ★★ 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-ser7trp (accessed [today's date]).

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