Is PMS2 p.Ser815Ter (c.2444C>A) pathogenic?

PMS2 p.Ser815Ter (c.2444C>A) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-25). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Ser815Ter (c.2444C>A)?

PMS2 p.Ser815Ter (c.2444C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser815Ter (c.2444C>A) in the general population?

PMS2 p.Ser815Ter (c.2444C>A) is absent from gnomAD v4.1 (gnomAD).

PMS2 p.Ser815Ter

c.2444C>A · rs587779338 · VCV1691167

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (14 of 15, 1 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Ser815Ter
Coding: c.2444C>A
MANE Select: NM_000535
dbSNP: rs587779338
Type: single nucleotide variant
Location: chr7:5977589 (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

Similar variants

PMS2 p.Ser815Leu Likely pathogenic ★★★ same residue
PMS2 p.Ser815= Conflicting classifications of pathogenicity ★ same residue
PMS2 p.Ser815_Val816insSerSerHisTer Pathogenic ★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.705+1G>T Likely pathogenic ★★★ same condition
PMS2 c.989-2A>G 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-ser815ter (accessed [today's date]).

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