Is PMS2 p.Pro247Ser (c.739C>T) pathogenic?

PMS2 p.Pro247Ser (c.739C>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-06). AlphaMissense: ambiguous (0.5353); Very rare (popmax 0.00017%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Pro247Ser (c.739C>T) in the general population?

PMS2 p.Pro247Ser (c.739C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Pro247Ser (c.739C>T)?

AlphaMissense predicts ambiguous (score 0.5353) — an in-silico prediction, not a clinical call.

PMS2 p.Pro247Ser

Q: What condition is associated with PMS2 p.Pro247Ser (c.739C>T)?

PMS2 p.Pro247Ser (c.739C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.739C>T · rs878854058 · VCV237926

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5353 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.5353	ambiguous
REVEL	0.667	pathogenic-leaning
SaProt	LLR -11.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	24.2	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 0.00017% European (non-Finnish) · 2/1,174,750 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,606,104 alleles · very rare exomes 2/1,455,292 · genomes 0/150,812 · 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.Pro247Ser
Coding: c.739C>T
MANE Select: NM_000535
dbSNP: rs878854058
Type: single nucleotide variant
Location: chr7:5997390 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 247: 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: hereditary neoplastic syndrome

Similar variants

PMS2 p.Pro247Ala Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro247Arg Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro247Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro247Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro247= Likely benign ★ same residue
PMS2 p.Pro247_Ser248insTer Pathogenic ★★ same residue
PMS2 p.Pro247fs Pathogenic ★★ same residue
PMS2 c.163+2T>C 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-pro247ser (accessed [today's date]).

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