Is PARP2 p.Arg140Pro (c.419G>C) pathogenic?

PARP2 p.Arg140Pro (c.419G>C) is classified Uncertain significance in PARP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.9886); Absent from gnomAD v4.1.

How common is PARP2 p.Arg140Pro (c.419G>C) in the general population?

PARP2 p.Arg140Pro (c.419G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PARP2 p.Arg140Pro (c.419G>C)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

PARP2 p.Arg140Pro

c.419G>C · VCV4564679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic · top 3% in PARP2
REVEL	0.667	pathogenic-leaning
SaProt	LLR -13.82	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 14 kb · p 0.15 · regional, not allelic
Overall
CADD	34.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R153P vs ClinVar R140P) — verify the residue.

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: PARP2
Protein: p.Arg140Pro
Coding: c.419G>C
MANE Select: NM_001042618
Type: single nucleotide variant
Location: chr14:20350620 (GRCh38)
Gene constraint: LOEUF 1.037 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.82 · 30 PDB
Residue 153 UniProt numbering: the wgr domain; a β-strand

Full PARP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PARP2 p.Asp222Gly Benign ★★ ⚠ same type
PARP2 p.Leu345= Benign ★★ same type
PARP2 p.Ser148Asn Benign ★★ same type
PARP2 c.202+13G>A Uncertain significance ★ ⚠ same type
PARP2 c.202+22C>T Uncertain significance ★ ⚠ same type
PARP2 c.202+37C>G Uncertain significance ★ ⚠ same type
PARP2 p.Ala14Thr Uncertain significance ★ ⚠ same type
PARP2 p.Ala323Ser Uncertain significance ★ ⚠ same type

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/parp2-p-arg140pro (accessed [today's date]).

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