Is MARS1 p.Pro41= (c.123G>C) pathogenic?

MARS1 p.Pro41= (c.123G>C) is classified Likely benign in MARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-16). Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2U.

What condition is associated with MARS1 p.Pro41= (c.123G>C)?

MARS1 p.Pro41= (c.123G>C) is associated with Charcot-Marie-Tooth disease axonal type 2U, severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (ClinVar).

How common is MARS1 p.Pro41= (c.123G>C) in the general population?

MARS1 p.Pro41= (c.123G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

MARS1 p.Pro41=

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

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

c.123G>C · rs2540254210 · VCV2126892

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2U

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.9	GERP -4
Overall
CADD	0.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,204 alleles

Overall 6.21e-05% 1/1,611,012 alleles · very rare exomes 1/1,461,342 · genomes 0/149,670 · joint denominator

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: MARS1
Protein: p.Pro41=
Coding: c.123G>C
MANE Select: NM_004990
dbSNP: rs2540254210
Type: single nucleotide variant
Location: chr12:57489032 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.61 · 7 PDB

Full MARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

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

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MARS1 c.1293+5G>A Uncertain significance ★★ same condition
MARS1 c.1967+3A>G Uncertain significance ★★ same condition
MARS1 p.Ala160Thr Uncertain significance ★★ ⚠ same condition
MARS1 p.Ala211Thr Uncertain significance ★★ ⚠ same condition
MARS1 p.Ala261Val Uncertain significance ★★ ⚠ same condition
MARS1 p.Ala397Thr Uncertain significance ★★ ⚠ same condition
MARS1 p.Ala765Val Uncertain significance ★★ ⚠ same condition
MARS1 p.Ala871Val 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/mars1-p-pro41 (accessed [today's date]).

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