Is AARS1 p.Arg329His (c.986G>A) pathogenic?

AARS1 p.Arg329His (c.986G>A) is classified Pathogenic/Likely pathogenic in AARS1 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 8.47e-05%, nfe); Associated with Hereditary neuropathy or pain disorder.

What condition is associated with AARS1 p.Arg329His (c.986G>A)?

AARS1 p.Arg329His (c.986G>A) is associated with Hereditary neuropathy or pain disorder, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease (ClinVar).

How common is AARS1 p.Arg329His (c.986G>A) in the general population?

AARS1 p.Arg329His (c.986G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Arg329His (c.986G>A)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

AARS1 p.Arg329His

c.986G>A · rs267606621 · VCV8466

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary neuropathy or pain disorder

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic ✓ concordant with ClinVar · top 10% in AARS1
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -15.33	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	33.0	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) · 1/1,179,990 alleles

Overall 0.000137% 2/1,461,816 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)grpmax	8.47e-05%	1,179,990

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg329His
Coding: c.986G>A
MANE Select: NM_001605
dbSNP: rs267606621
Type: single nucleotide variant
Location: chr16:70268356 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 329: a UniProt-annotated variant site (in cmt2n; severely reduces enzyme activity); an α-helix

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

Disease context

Hereditary neuropathy or pain disorder

Also linked: Charcot-Marie-Tooth disease axonal type 2N Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 2

Similar variants

AARS1 p.Arg329Cys Likely pathogenic ★★ 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.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg333Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg598Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Gly102Arg 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-arg329his (accessed [today's date]).

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