Is MARS1 p.Ser712Pro (c.2134T>C) pathogenic?

MARS1 p.Ser712Pro (c.2134T>C) is classified Uncertain significance in MARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2U.

What condition is associated with MARS1 p.Ser712Pro (c.2134T>C)?

MARS1 p.Ser712Pro (c.2134T>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.Ser712Pro (c.2134T>C) in the general population?

MARS1 p.Ser712Pro (c.2134T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MARS1 p.Ser712Pro (c.2134T>C)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

MARS1 p.Ser712Pro

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.2134T>C · rs2540318916 · VCV2043888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease axonal type 2U

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic · top 6% in MARS1
REVEL	0.494	indeterminate
SaProt	LLR -13.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 28 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	27.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MARS1
Protein: p.Ser712Pro
Coding: c.2134T>C
MANE Select: NM_004990
dbSNP: rs2540318916
Type: single nucleotide variant
Location: chr12:57514988 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.61 · 7 PDB
Residue 712: 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 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-ser712pro (accessed [today's date]).

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