Is MARS2 p.Pro302Ser (c.904C>T) pathogenic?

MARS2 p.Pro302Ser (c.904C>T) is classified Uncertain significance in MARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: ambiguous (0.34); Very rare (popmax 0.00833%, amr).

How common is MARS2 p.Pro302Ser (c.904C>T) in the general population?

MARS2 p.Pro302Ser (c.904C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about MARS2 p.Pro302Ser (c.904C>T)?

AlphaMissense predicts ambiguous (score 0.34) — an in-silico prediction, not a clinical call.

MARS2 p.Pro302Ser

c.904C>T · VCV4726688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.34 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.34	ambiguous
REVEL	0.246	benign-leaning
SaProt	LLR -5.14	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,778 bp · p 0.12 · regional, not allelic
Overall
CADD	22.7	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 0.00833% Admixed American · 5/60,012 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000743% 12/1,614,096 alleles · very rare exomes 10/1,461,864 · genomes 2/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,002
European (non-Finnish)	0.000593%	168,579

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: MARS2
Protein: p.Pro302Ser
Coding: c.904C>T
MANE Select: NM_138395
Type: single nucleotide variant
Location: chr2:197706309 (GRCh38)
Gene constraint: LOEUF 0.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.66

Full MARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARS2 p.Pro302Ala Uncertain significance ★ ⚠ same residue
MARS2 p.Ala141Val Uncertain significance ★★ ⚠ same type
MARS2 p.Ala402Ser Uncertain significance ★★ ⚠ same type
MARS2 p.Arg142Trp Uncertain significance ★★ ⚠ same type
MARS2 p.Arg224Gln Uncertain significance ★★ ⚠ same type
MARS2 p.Arg409Gly Uncertain significance ★★ ⚠ same type
MARS2 p.Arg414Ile Uncertain significance ★★ ⚠ same type
MARS2 p.Arg568Gly Uncertain significance ★★ ⚠ same type

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/mars2-p-pro302ser (accessed [today's date]).

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