Is AARS1 p.Pro129Ala (c.385C>G) pathogenic?

AARS1 p.Pro129Ala (c.385C>G) is classified Conflicting classifications of pathogenicity in AARS1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1565); Ultra-rare (popmax 0.033%, mid); Associated with Charcot-Marie-Tooth disease.

What condition is associated with AARS1 p.Pro129Ala (c.385C>G)?

AARS1 p.Pro129Ala (c.385C>G) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Pro129Ala (c.385C>G) in the general population?

AARS1 p.Pro129Ala (c.385C>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about AARS1 p.Pro129Ala (c.385C>G)?

AlphaMissense predicts likely benign (score 0.1565) — an in-silico prediction, not a clinical call.

AARS1 p.Pro129Ala

c.385C>G · rs370622071 · VCV246216

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.1565	likely benign
REVEL	0.39	indeterminate
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.71, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	21.6	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00626% 101/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.0096%	10,417
European (non-Finnish)	0.00593%	16,857
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,517
South Asian	0.0011%	91,082

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.Pro129Ala
Coding: c.385C>G
MANE Select: NM_001605
dbSNP: rs370622071
Type: single nucleotide variant
Location: chr16:70276580 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 2

Similar variants

AARS1 p.Pro129Leu Uncertain significance ★ ⚠ same residue
AARS1 p.Pro129= Likely benign ★ 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-pro129ala (accessed [today's date]).

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