Is PMS2 p.Ser815= (c.2445G>A) pathogenic?

PMS2 p.Ser815= (c.2445G>A) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-30). Ultra-rare (popmax 0.0348%, mid); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ser815= (c.2445G>A)?

PMS2 p.Ser815= (c.2445G>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Ser815= (c.2445G>A) in the general population?

PMS2 p.Ser815= (c.2445G>A) is ultra-rare (popmax 0.0348%, mid) (gnomAD).

PMS2 p.Ser815=

c.2445G>A · rs753199796 · VCV184485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0348%, mid)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.005	phastCons 0.032
Overall
CADD	9.511	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0348% Middle Eastern · 2/5,746 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.0064% 99/1,546,312 alleles · ultra-rare exomes 82/1,397,594 · genomes 17/148,718 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0348%	2,873
Admixed American	0.0325%	3,073
Remaining individualsnot grpmax-eligible	0.0199%	5,015
African / African-American	0.00546%	18,316
European (non-Finnish)	0.00534%	18,734
South Asian	0.00226%	44,291

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.Ser815=
Coding: c.2445G>A
MANE Select: NM_000535
dbSNP: rs753199796
Type: single nucleotide variant
Location: chr7:5977588 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 815: a UniProt-annotated variant site (in mmrcs4; decreased dna mismatch repair activity)

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 4 hereditary neoplastic syndrome mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Ser815Leu Likely pathogenic ★★★ same residue
PMS2 p.Ser815Ter Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Ser815_Val816insSerSerHisTer 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
PMS2 c.2174+1G>A 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-ser815 (accessed [today's date]).

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