Is MARS1 p.Pro46Arg (c.137C>G) pathogenic?

MARS1 p.Pro46Arg (c.137C>G) is classified Uncertain significance in MARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-19). AlphaMissense: likely benign (0.1864); Very rare (popmax 0.0011%, sas); Associated with severe early-onset pulmonary alveolar proteinosis due to MARS deficiency.

How common is MARS1 p.Pro46Arg (c.137C>G) in the general population?

MARS1 p.Pro46Arg (c.137C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MARS1 p.Pro46Arg (c.137C>G)?

AlphaMissense predicts likely benign (score 0.1864) — an in-silico prediction, not a clinical call.

MARS1 p.Pro46Arg

Q: What condition is associated with MARS1 p.Pro46Arg (c.137C>G)?

MARS1 p.Pro46Arg (c.137C>G) is associated with severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, Charcot-Marie-Tooth disease axonal type 2U (ClinVar).

Q: How is Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency inherited?

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

c.137C>G · rs767326124 · VCV2945493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Computational evidence

Protein change
AlphaMissense	0.1864	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 28 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0011% South Asian · 1/91,090 alleles

Overall 6.2e-05% 1/1,613,980 alleles · very rare exomes 1/1,461,860 · genomes 0/152,120 · 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.Pro46Arg
Coding: c.137C>G
MANE Select: NM_004990
dbSNP: rs767326124
Type: single nucleotide variant
Location: chr12:57489046 (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

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2U

For Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MARS1 p.Pro46Ser Uncertain significance ★ ⚠ same residue
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

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-pro46arg (accessed [today's date]).

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