Is FARS2 p.Ala235= (c.705C>T) pathogenic?

FARS2 p.Ala235= (c.705C>T) is classified Likely benign in FARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). Ultra-rare (popmax 0.0374%, sas); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Ala235= (c.705C>T)?

FARS2 p.Ala235= (c.705C>T) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Ala235= (c.705C>T) in the general population?

FARS2 p.Ala235= (c.705C>T) is ultra-rare (popmax 0.0374%, sas) (gnomAD).

FARS2 p.Ala235=

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.705C>T · rs766636921 · VCV1616644

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, sas)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.2	GERP -2.3
Overall
CADD	10.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0374% South Asian · 34/90,834 alleles

Filtering AF 0.0275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0241%

Overall 0.00279% 45/1,612,794 alleles · ultra-rare exomes 44/1,460,622 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0374%	2,672
Admixed American	0.00501%	19,980
Remaining individualsnot grpmax-eligible	0.0032%	31,211
East Asian	0.00223%	44,886
European (non-Finnish)	0.000424%	235,857

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.Ala235=
Coding: c.705C>T
MANE Select: NM_006567
dbSNP: rs766636921
Type: single nucleotide variant
Location: chr6:5404634 (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 235: 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.Ala235Val 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
FARS2 p.Gly309Ser 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-ala235 (accessed [today's date]).

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