Is MARS1 p.Phe4= (c.12C>T) pathogenic?

MARS1 p.Phe4= (c.12C>T) is classified Likely benign in MARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). Very rare (popmax 0.00446%, eas); Associated with severe early-onset pulmonary alveolar proteinosis due to MARS deficiency.

How common is MARS1 p.Phe4= (c.12C>T) in the general population?

MARS1 p.Phe4= (c.12C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

MARS1 p.Phe4=

Q: What condition is associated with MARS1 p.Phe4= (c.12C>T)?

MARS1 p.Phe4= (c.12C>T) 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.12C>T · VCV3764053

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.094	GERP -2.9, phastCons 0.54
Overall
CADD	10.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,613,958 alleles · very rare exomes 2/1,461,760 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
African / African-American	0.00267%	37,463
Admixed American	0.00167%	60,002
European (non-Finnish)	8.47e-05%	1,179,972

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.Phe4=
Coding: c.12C>T
MANE Select: NM_004990
Type: single nucleotide variant
Location: chr12:57488102 (GRCh38)

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

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-phe4 (accessed [today's date]).

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