Is MARS2 p.Ser418Phe (c.1253C>T) pathogenic?

MARS2 p.Ser418Phe (c.1253C>T) is classified Uncertain significance in MARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1746); Ultra-rare (popmax 0.0667%, amr).

How common is MARS2 p.Ser418Phe (c.1253C>T) in the general population?

MARS2 p.Ser418Phe (c.1253C>T) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about MARS2 p.Ser418Phe (c.1253C>T)?

AlphaMissense predicts likely benign (score 0.1746) — an in-silico prediction, not a clinical call.

MARS2 p.Ser418Phe

c.1253C>T · rs767717981 · VCV1199887

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1746	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 0.72
Regional constraint	o/e 0.94	unconstrained · MANE · 1,778 bp · p 0.12 · regional, not allelic
Overall
CADD	24.6	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 0.0667% Admixed American · 40/60,010 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.00254% 41/1,614,110 alleles · ultra-rare exomes 38/1,461,858 · genomes 3/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
European (non-Finnish)	8.47e-05%	1,180,050

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.Ser418Phe
Coding: c.1253C>T
MANE Select: NM_138395
dbSNP: rs767717981
Type: single nucleotide variant
Location: chr2:197706658 (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-ser418phe (accessed [today's date]).

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