Is PARS2 p.Pro293Ala (c.877C>G) pathogenic?

PARS2 p.Pro293Ala (c.877C>G) is classified Likely pathogenic in PARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.0849); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 75.

What condition is associated with PARS2 p.Pro293Ala (c.877C>G)?

PARS2 p.Pro293Ala (c.877C>G) is associated with developmental and epileptic encephalopathy, 75 (ClinVar).

How common is PARS2 p.Pro293Ala (c.877C>G) in the general population?

PARS2 p.Pro293Ala (c.877C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PARS2 p.Pro293Ala (c.877C>G)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

PARS2 p.Pro293Ala

c.877C>G · VCV3767223

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 75

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign ⚠ discordant with ClinVar
REVEL	0.199	benign-leaning
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 1,424 bp · p 0.49 · regional, not allelic
Overall
CADD	25.2	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

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: PARS2
Protein: p.Pro293Ala
Coding: c.877C>G
MANE Select: NM_152268
Type: single nucleotide variant
Location: chr1:54758285 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30

Full PARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 75 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PARS2 p.Pro293Arg Uncertain significance ★ ⚠ same residue
PARS2 p.Gln296Ter Likely pathogenic ★★ same condition
PARS2 p.Arg96His Uncertain significance ★★ ⚠ same condition
PARS2 p.Cys292Arg Uncertain significance ★★ ⚠ same condition
PARS2 p.Gly114Ser Uncertain significance ★★ ⚠ same condition
PARS2 p.Lys236Glu Uncertain significance ★★ ⚠ same condition
PARS2 p.Met98Ile Uncertain significance ★★ ⚠ same condition
PARS2 p.Pro377Ala Uncertain significance ★★ ⚠ 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/pars2-p-pro293ala (accessed [today's date]).

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