Is PMS2 p.Asp60Glu (c.180C>G) pathogenic?

PMS2 p.Asp60Glu (c.180C>G) is classified Likely benign in PMS2 (ClinVar, Expert panel, 26 submitters; last evaluated 2013-09-05). AlphaMissense: likely benign (0.1449); Ultra-rare (popmax 0.0613%, nfe); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Asp60Glu (c.180C>G)?

PMS2 p.Asp60Glu (c.180C>G) is associated with Lynch syndrome, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Asp60Glu (c.180C>G) in the general population?

PMS2 p.Asp60Glu (c.180C>G) is ultra-rare (popmax 0.0613%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PMS2 p.Asp60Glu (c.180C>G)?

AlphaMissense predicts likely benign (score 0.1449) — an in-silico prediction, not a clinical call.

PMS2 p.Asp60Glu

c.180C>G · rs200313585 · VCV91315

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 26 submitters

AlphaMissense

likely benign

0.1449 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.1449	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -5.01	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 1.5	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	14.74	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 0.0613% European (non-Finnish) · 710/1,157,308 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.0731% 1,159/1,586,516 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.616%	162
Remaining individualsnot grpmax-eligible	0.0651%	1,535
European (non-Finnish)grpmax	0.0613%	1,630
African / African-American	0.0121%	8,246
Admixed American	0.01%	9,982

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp60Glu
Coding: c.180C>G
MANE Select: NM_000535
dbSNP: rs200313585
Type: single nucleotide variant
Location: chr7:6004042 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 60: a UniProt-annotated variant site (normal dna mismatch repair activity); an α-helix

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Asp60Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp60Ala Uncertain significance ★ ⚠ 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-asp60glu (accessed [today's date]).

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