Is AARS1 p.Phe958Ser (c.2873T>C) pathogenic?

AARS1 p.Phe958Ser (c.2873T>C) is classified Likely pathogenic in AARS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-04-25). AlphaMissense: likely pathogenic (0.9491); Very rare (popmax 8.47e-05%, nfe); Associated with developmental and epileptic encephalopathy, 29.

What condition is associated with AARS1 p.Phe958Ser (c.2873T>C)?

AARS1 p.Phe958Ser (c.2873T>C) is associated with developmental and epileptic encephalopathy, 29 (ClinVar).

How common is AARS1 p.Phe958Ser (c.2873T>C) in the general population?

AARS1 p.Phe958Ser (c.2873T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Phe958Ser (c.2873T>C)?

AlphaMissense predicts likely pathogenic (score 0.9491) — an in-silico prediction, not a clinical call.

AARS1 p.Phe958Ser

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.2873T>C · rs1555539157 · VCV549676

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 29

Computational evidence

Protein change
AlphaMissense	0.9491	likely pathogenic ✓ concordant with ClinVar
REVEL	0.692	pathogenic-leaning
SaProt	LLR -11.74	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	27.2	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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,840 alleles · very rare

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: AARS1
Protein: p.Phe958Ser
Coding: c.2873T>C
MANE Select: NM_001605
dbSNP: rs1555539157
Type: single nucleotide variant
Location: chr16:70252755 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 958: an α-helix

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.Phe958Leu Uncertain significance ★★ ⚠ same residue
AARS1 p.Phe958= Likely benign ★ same residue
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

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-phe958ser (accessed [today's date]).

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