Is FARS2 p.Asp169Val (c.506A>T) pathogenic?

FARS2 p.Asp169Val (c.506A>T) is classified Conflicting classifications of pathogenicity in FARS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.4745); Rare (popmax 0.487%, afr); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Asp169Val (c.506A>T)?

FARS2 p.Asp169Val (c.506A>T) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Asp169Val (c.506A>T) in the general population?

FARS2 p.Asp169Val (c.506A>T) is rare (popmax 0.487%, afr) (gnomAD).

What do computational predictors say about FARS2 p.Asp169Val (c.506A>T)?

AlphaMissense predicts ambiguous (score 0.4745) — an in-silico prediction, not a clinical call.

FARS2 p.Asp169Val

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.506A>T · rs146356199 · VCV214338

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4745 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.487%, afr)

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
AlphaMissense	0.4745	ambiguous
REVEL	0.295	indeterminate
SaProt	LLR -11.88	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · 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 0.487% African / African-American · 365/74,974 alleles

Filtering AF 0.446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.429%

Overall 0.025% 404/1,613,932 alleles · rare exomes 206/1,461,778 · genomes 198/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.487%	205
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.0183%	5,457
European (non-Finnish)	0.00119%	84,284

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.Asp169Val
Coding: c.506A>T
MANE Select: NM_006567
dbSNP: rs146356199
Type: single nucleotide variant
Location: chr6:5369076 (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 169: a β-strand

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-asp169val (accessed [today's date]).

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