Is AARS1 p.Arg320His (c.959G>A) pathogenic?

AARS1 p.Arg320His (c.959G>A) is classified Uncertain significance in AARS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9436); Ultra-rare (popmax 0.0395%, sas); Associated with developmental and epileptic encephalopathy, 29.

What condition is associated with AARS1 p.Arg320His (c.959G>A)?

AARS1 p.Arg320His (c.959G>A) is associated with developmental and epileptic encephalopathy, 29, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Arg320His (c.959G>A) in the general population?

AARS1 p.Arg320His (c.959G>A) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about AARS1 p.Arg320His (c.959G>A)?

AlphaMissense predicts likely pathogenic (score 0.9436) — an in-silico prediction, not a clinical call.

AARS1 p.Arg320His

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.959G>A · rs557600847 · VCV476746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 29

Computational evidence

Protein change
AlphaMissense	0.9436	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	27.7	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 0.0395% South Asian · 36/91,088 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0044% 71/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Middle Eastern	0.0165%	6,062
Admixed American	0.00666%	15,004
European (non-Finnish)	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,506
Finnishnot grpmax-eligible	0.00157%	63,852

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.Arg320His
Coding: c.959G>A
MANE Select: NM_001605
dbSNP: rs557600847
Type: single nucleotide variant
Location: chr16:70269621 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 320: 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

Also linked: Charcot-Marie-Tooth disease axonal type 2N Charcot-Marie-Tooth disease type 2 trichothiodystrophy 8, nonphotosensitive leukoencephalopathy, hereditary diffuse, with spheroids 2

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

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

Similar variants

AARS1 p.Arg320Cys Uncertain significance ★★ ⚠ same residue
AARS1 p.Arg320Gly Uncertain significance ★★ ⚠ same residue
AARS1 c.2177+1G>A Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg13Ter Pathogenic ★★ same condition
AARS1 p.Arg246Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg329Cys Likely pathogenic ★★ same condition
AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg330Ter Pathogenic/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/aars1-p-arg320his (accessed [today's date]).

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