Is FARS2 p.Phe402Ser (c.1205T>C) pathogenic?

FARS2 p.Phe402Ser (c.1205T>C) is classified Likely pathogenic in FARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.9428); Very rare (popmax 8.48e-05%, nfe); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Phe402Ser (c.1205T>C)?

FARS2 p.Phe402Ser (c.1205T>C) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Phe402Ser (c.1205T>C) in the general population?

FARS2 p.Phe402Ser (c.1205T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about FARS2 p.Phe402Ser (c.1205T>C)?

AlphaMissense predicts likely pathogenic (score 0.9428) — an in-silico prediction, not a clinical call.

FARS2 p.Phe402Ser

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.1205T>C · VCV4750124

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
AlphaMissense	0.9428	likely pathogenic ✓ concordant with ClinVar · top 7% in FARS2
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 0.35, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	28.5	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 8.48e-05% European (non-Finnish) · 1/1,179,566 alleles

Overall 6.2e-05% 1/1,612,870 alleles · very rare exomes 1/1,460,532 · genomes 0/152,338 · 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.Phe402Ser
Coding: c.1205T>C
MANE Select: NM_006567
Type: single nucleotide variant
Location: chr6:5613308 (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 402: the fdx-acb domain; 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-phe402ser (accessed [today's date]).

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