Is AARS1 p.Arg326Pro (c.977G>C) pathogenic?

AARS1 p.Arg326Pro (c.977G>C) is classified Pathogenic in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.000339%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2N.

What condition is associated with AARS1 p.Arg326Pro (c.977G>C)?

AARS1 p.Arg326Pro (c.977G>C) is associated with Charcot-Marie-Tooth disease axonal type 2N (ClinVar).

How common is AARS1 p.Arg326Pro (c.977G>C) in the general population?

AARS1 p.Arg326Pro (c.977G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Arg326Pro (c.977G>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

AARS1 p.Arg326Pro

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2N inherited?

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

c.977G>C · rs2152160758 · VCV1685482

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2N

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar · top 2% in AARS1
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -15.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	34.0	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 0.000339% European (non-Finnish) · 4/1,179,974 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,768 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.Arg326Pro
Coding: c.977G>C
MANE Select: NM_001605
dbSNP: rs2152160758
Type: single nucleotide variant
Location: chr16:70268365 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 326: a UniProt-annotated variant site (in cmt2n); an α-helix

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

Disease context

Charcot-Marie-Tooth disease axonal type 2N — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2N (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

AARS1 p.Arg326Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
AARS1 p.Arg326Gln Likely pathogenic same residue
AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Trp104Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Tyr322Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Ala866Thr Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg320His Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg616Cys 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-arg326pro (accessed [today's date]).

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