Is PMS2 p.Ser36Arg (c.106A>C) pathogenic?

PMS2 p.Ser36Arg (c.106A>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.8831); Very rare (popmax 0.00526%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ser36Arg (c.106A>C) in the general population?

PMS2 p.Ser36Arg (c.106A>C) is very rare (popmax 0.00526%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Ser36Arg (c.106A>C)?

AlphaMissense predicts likely pathogenic (score 0.8831) — an in-silico prediction, not a clinical call.

PMS2 p.Ser36Arg

Q: What condition is associated with PMS2 p.Ser36Arg (c.106A>C)?

PMS2 p.Ser36Arg (c.106A>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.106A>C · rs587781918 · VCV141660

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00526%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.8831	likely pathogenic
REVEL	0.653	pathogenic-leaning
SaProt	LLR -12.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00526% European (non-Finnish) · 62/1,179,826 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00385% 62/1,610,716 alleles · very rare exomes 61/1,458,522 · genomes 1/152,194 · joint denominator

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.Ser36Arg
Coding: c.106A>C
MANE Select: NM_000535
dbSNP: rs587781918
Type: single nucleotide variant
Location: chr7:6005949 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 36: a UniProt-annotated variant site (no effect on protein levels); an α-helix

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 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Ser36Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser36Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser36= Benign/Likely benign ★★ same residue
PMS2 p.Ser36Cys 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-ser36arg (accessed [today's date]).

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