Is FARS2 p.Arg7Ser (c.21G>T) pathogenic?

FARS2 p.Arg7Ser (c.21G>T) is classified Conflicting classifications of pathogenicity in FARS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-11). AlphaMissense: likely benign (0.1689); Ultra-rare (popmax 0.0401%, eas); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Arg7Ser (c.21G>T)?

FARS2 p.Arg7Ser (c.21G>T) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Arg7Ser (c.21G>T) in the general population?

FARS2 p.Arg7Ser (c.21G>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about FARS2 p.Arg7Ser (c.21G>T)?

AlphaMissense predicts likely benign (score 0.1689) — an in-silico prediction, not a clinical call.

FARS2 p.Arg7Ser

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.21G>T · rs764390927 · VCV571907

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
AlphaMissense	0.1689	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.85	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 0.44	GERP -3.3, phastCons 0.91
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	7.213	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 0.0401% East Asian · 18/44,840 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00112% 18/1,612,768 alleles · ultra-rare exomes 14/1,460,474 · genomes 4/152,294 · 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.Arg7Ser
Coding: c.21G>T
MANE Select: NM_006567
dbSNP: rs764390927
Type: single nucleotide variant
Location: chr6:5368591 (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.Arg7Lys Uncertain significance ★ ⚠ same residue
LYRM4 p.Ala7Thr Uncertain significance ★★ ⚠ 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
FARS2 p.Gln216Ter 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-arg7ser (accessed [today's date]).

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