Is MARS1 p.Pro433Ser (c.1297C>T) pathogenic?

MARS1 p.Pro433Ser (c.1297C>T) is classified Uncertain significance in MARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-07). AlphaMissense: likely pathogenic (0.672); Very rare (popmax 0.000254%, nfe); Associated with severe early-onset pulmonary alveolar proteinosis due to MARS deficiency.

How common is MARS1 p.Pro433Ser (c.1297C>T) in the general population?

MARS1 p.Pro433Ser (c.1297C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MARS1 p.Pro433Ser (c.1297C>T)?

AlphaMissense predicts likely pathogenic (score 0.672) — an in-silico prediction, not a clinical call.

MARS1 p.Pro433Ser

Q: What condition is associated with MARS1 p.Pro433Ser (c.1297C>T)?

MARS1 p.Pro433Ser (c.1297C>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.1297C>T · rs1450179852 · VCV1681728

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Computational evidence

Protein change
AlphaMissense	0.672	likely pathogenic
REVEL	0.469	indeterminate
SaProt	LLR -11.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 28 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	26.8	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 0.000254% European (non-Finnish) · 3/1,179,674 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,644 alleles · very rare exomes 2/1,461,466 · genomes 1/152,178 · 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.Pro433Ser
Coding: c.1297C>T
MANE Select: NM_004990
dbSNP: rs1450179852
Type: single nucleotide variant
Location: chr12:57504228 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.61 · 7 PDB
Residue 433: a β-strand

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 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-pro433ser (accessed [today's date]).

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