Is FARS2 p.Arg338= (c.1014C>T) pathogenic?

FARS2 p.Arg338= (c.1014C>T) is classified Benign/Likely benign in FARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-15). Rare (popmax 0.198%, mid); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Arg338= (c.1014C>T)?

FARS2 p.Arg338= (c.1014C>T) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Arg338= (c.1014C>T) in the general population?

FARS2 p.Arg338= (c.1014C>T) is rare (popmax 0.198%, mid) (gnomAD).

FARS2 p.Arg338=

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.1014C>T · rs41302855 · VCV587662

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3
Overall
CADD	4.727	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.198% Middle Eastern · 12/6,062 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0895%

Overall 0.00712% 115/1,614,110 alleles · rare exomes 97/1,461,812 · genomes 18/152,298 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	505
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)	0.0072%	13,882
South Asian	0.00549%	18,214
African / African-American	0.004%	25,017
Admixed American	0.00167%	60,026
Finnishnot grpmax-eligible	0.00156%	64,020

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.Arg338=
Coding: c.1014C>T
MANE Select: NM_006567
dbSNP: rs41302855
Type: single nucleotide variant
Location: chr6:5545289 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.17 · 9 PDB
Residue 338: an α-helix

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.Arg338Cys Uncertain significance ★★ ⚠ same residue
FARS2 p.Arg338Ser Uncertain significance ★★ same residue
FARS2 p.Arg338His Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg338 (accessed [today's date]).

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