Is MARS1 p.Pro329His (c.986C>A) pathogenic?

MARS1 p.Pro329His (c.986C>A) is classified Conflicting classifications of pathogenicity in MARS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9309); Rare (popmax 0.139%, afr); Associated with Charcot-Marie-Tooth disease axonal type 2U.

What condition is associated with MARS1 p.Pro329His (c.986C>A)?

MARS1 p.Pro329His (c.986C>A) 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.Pro329His (c.986C>A) in the general population?

MARS1 p.Pro329His (c.986C>A) is rare (popmax 0.139%, afr) (gnomAD).

What do computational predictors say about MARS1 p.Pro329His (c.986C>A)?

AlphaMissense predicts likely pathogenic (score 0.9309) — an in-silico prediction, not a clinical call.

MARS1 p.Pro329His

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.986C>A · rs145260922 · VCV859475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9309 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2U

Computational evidence

Protein change
AlphaMissense	0.9309	likely pathogenic
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -16.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 28 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.139% African / African-American · 104/75,046 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.00706% 114/1,614,170 alleles · rare exomes 61/1,461,876 · genomes 53/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.139%	722
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.00667%	15,004

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.Pro329His
Coding: c.986C>A
MANE Select: NM_004990
dbSNP: rs145260922
Type: single nucleotide variant
Location: chr12:57498518 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.61 · 7 PDB
Residue 329: an α-helix

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 p.Pro329Leu Uncertain significance ★★ ⚠ same residue
MARS1 p.Pro329Ala Uncertain significance ★ ⚠ same residue
MARS1 p.Pro329Thr 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

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-pro329his (accessed [today's date]).

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