Is MARS2 p.Cys175Ser (c.523T>A) pathogenic?

MARS2 p.Cys175Ser (c.523T>A) is classified Uncertain significance in MARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-16). AlphaMissense: likely benign (0.1889); Very rare (popmax 0.00666%, amr).

How common is MARS2 p.Cys175Ser (c.523T>A) in the general population?

MARS2 p.Cys175Ser (c.523T>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about MARS2 p.Cys175Ser (c.523T>A)?

AlphaMissense predicts likely benign (score 0.1889) — an in-silico prediction, not a clinical call.

MARS2 p.Cys175Ser

c.523T>A · rs777557546 · VCV2210644

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1889	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -2.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,778 bp · p 0.12 · regional, not allelic
Overall
CADD	19.77	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,070 alleles · very rare exomes 4/1,461,850 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
European (non-Finnish)	8.47e-05%	1,180,043

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.Cys175Ser
Coding: c.523T>A
MANE Select: NM_138395
dbSNP: rs777557546
Type: single nucleotide variant
Location: chr2:197705928 (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.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
MARS2 p.Arg592Gln 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-cys175ser (accessed [today's date]).

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