Is AARS1 p.Pro596Ser (c.1786C>T) pathogenic?

AARS1 p.Pro596Ser (c.1786C>T) is classified Uncertain significance in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-03). AlphaMissense: likely benign (0.091); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 29.

What condition is associated with AARS1 p.Pro596Ser (c.1786C>T)?

AARS1 p.Pro596Ser (c.1786C>T) is associated with developmental and epileptic encephalopathy, 29 (ClinVar).

How common is AARS1 p.Pro596Ser (c.1786C>T) in the general population?

AARS1 p.Pro596Ser (c.1786C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AARS1 p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

AARS1 p.Pro596Ser

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1786C>T · rs780249378 · VCV1299302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 29

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -3.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP -0.68, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	15.78	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: AARS1
Protein: p.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_001605
dbSNP: rs780249378
Type: single nucleotide variant
Location: chr16:70259186 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB

Full AARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

AARS1 p.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Ala78Ser Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg296Gln Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg320His Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg750Trp Uncertain significance ★★ ⚠ same condition
AARS1 p.Asn657Asp Uncertain significance ★★ ⚠ same condition
AARS1 p.Asp87Asn Uncertain significance ★★ ⚠ same condition
AARS1 p.Tyr25Cys 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/aars1-p-pro596ser (accessed [today's date]).

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