Is AARS1 p.Ala951Thr (c.2851G>A) pathogenic?

AARS1 p.Ala951Thr (c.2851G>A) is classified Uncertain significance in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.2458); Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2N.

What condition is associated with AARS1 p.Ala951Thr (c.2851G>A)?

AARS1 p.Ala951Thr (c.2851G>A) is associated with Charcot-Marie-Tooth disease axonal type 2N (ClinVar).

How common is AARS1 p.Ala951Thr (c.2851G>A) in the general population?

AARS1 p.Ala951Thr (c.2851G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Ala951Thr (c.2851G>A)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

AARS1 p.Ala951Thr

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.2851G>A · VCV3774579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2N

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -9.28	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, 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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 6.84e-05% 1/1,461,860 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.Ala951Thr
Coding: c.2851G>A
MANE Select: NM_001605
Type: single nucleotide variant
Location: chr16:70252777 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 951: 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.Ala951= Likely benign ★ 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
AARS1 p.Arg633Cys 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-ala951thr (accessed [today's date]).

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