Is FARS2 p.Pro405Ser (c.1213C>T) pathogenic?

FARS2 p.Pro405Ser (c.1213C>T) is classified Uncertain significance in FARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2742); Very rare (popmax 0.000254%, nfe); Associated with combined oxidative phosphorylation defect type 14.

What condition is associated with FARS2 p.Pro405Ser (c.1213C>T)?

FARS2 p.Pro405Ser (c.1213C>T) is associated with combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Pro405Ser (c.1213C>T) in the general population?

FARS2 p.Pro405Ser (c.1213C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about FARS2 p.Pro405Ser (c.1213C>T)?

AlphaMissense predicts likely benign (score 0.2742) — an in-silico prediction, not a clinical call.

FARS2 p.Pro405Ser

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.1213C>T · rs1775291666 · VCV1472378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

combined oxidative phosphorylation defect type 14

Computational evidence

Protein change
AlphaMissense	0.2742	likely benign
REVEL	0.576	indeterminate
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,178,810 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,232 alleles · very rare exomes 3/1,458,982 · genomes 0/152,250 · 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.Pro405Ser
Coding: c.1213C>T
MANE Select: NM_006567
dbSNP: rs1775291666
Type: single nucleotide variant
Location: chr6:5613316 (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 405: the fdx-acb domain; a turn

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-pro405ser (accessed [today's date]).

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