Is FARS2 p.Met1Val (c.1A>G) pathogenic?

FARS2 p.Met1Val (c.1A>G) is classified Pathogenic in FARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). Very rare (popmax 0.000511%, nfe); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Met1Val (c.1A>G)?

FARS2 p.Met1Val (c.1A>G) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Met1Val (c.1A>G) in the general population?

FARS2 p.Met1Val (c.1A>G) is very rare (popmax 0.000511%, nfe) (gnomAD).

FARS2 p.Met1Val

Q: How is Combined oxidative phosphorylation defect type 14 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1A>G · VCV3666334

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000511%, nfe)

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.339	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.5, phastCons 1
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000511% European (non-Finnish) · 6/1,173,994 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000374% 6/1,604,248 alleles · very rare exomes 6/1,451,954 · genomes 0/152,294 · joint denominator

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: FARS2
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_006567
Type: single nucleotide variant
Location: chr6:5368571 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.17 · 9 PDB

Full FARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 14 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FARS2 p.Arg307Ter Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Arg386Ter Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Arg419Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
FARS2 p.Arg419His Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Gln100Ter Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Gln216Ter Pathogenic ★★ same condition
FARS2 p.Gly309Ser Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Pro361Leu Pathogenic/Likely pathogenic ★★ 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/fars2-p-met1val (accessed [today's date]).

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