Is AARS1 p.Pro421Ala (c.1261C>G) pathogenic?

AARS1 p.Pro421Ala (c.1261C>G) is classified Uncertain significance in AARS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-27). AlphaMissense: likely pathogenic (0.9886); Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Pro421Ala (c.1261C>G)?

AARS1 p.Pro421Ala (c.1261C>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Pro421Ala (c.1261C>G) in the general population?

AARS1 p.Pro421Ala (c.1261C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AARS1 p.Pro421Ala (c.1261C>G)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

AARS1 p.Pro421Ala

c.1261C>G · rs1157450521 · VCV654287

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -11.46	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,984 alleles

Overall 0.00041% 6/1,461,720 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,500
Admixed Americangrpmax	0.00167%	59,984

Remaining individuals 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.Pro421Ala
Coding: c.1261C>G
MANE Select: NM_001605
dbSNP: rs1157450521
Type: single nucleotide variant
Location: chr16:70265624 (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 type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS1 p.Pro421Leu Uncertain significance ★ ⚠ same residue
AARS1 p.Pro421= 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-pro421ala (accessed [today's date]).

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