Is FARS2 p.Arg330Cys (c.988C>T) pathogenic?

FARS2 p.Arg330Cys (c.988C>T) is classified Uncertain significance in FARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.5525); Very rare (popmax 0.00667%, amr); Associated with hereditary spastic paraplegia 77.

What condition is associated with FARS2 p.Arg330Cys (c.988C>T)?

FARS2 p.Arg330Cys (c.988C>T) is associated with hereditary spastic paraplegia 77, combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.Arg330Cys (c.988C>T) in the general population?

FARS2 p.Arg330Cys (c.988C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 77 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FARS2 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts ambiguous (score 0.5525) — an in-silico prediction, not a clinical call.

FARS2 p.Arg330Cys

c.988C>T · rs757442324 · VCV944163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary spastic paraplegia 77

Computational evidence

Protein change
AlphaMissense	0.5525	ambiguous
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -14.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	33.0	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 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00112% 18/1,613,900 alleles · very rare exomes 16/1,461,732 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
East Asian	0.00445%	22,448
South Asian	0.0011%	91,084
European (non-Finnish)	0.000932%	107,265

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.Arg330Cys
Coding: c.988C>T
MANE Select: NM_006567
dbSNP: rs757442324
Type: single nucleotide variant
Location: chr6:5545263 (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 330: an α-helix

Full FARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 77 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation defect type 14

For Autosomal recessive spastic paraplegia type 77 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

FARS2 p.Arg330His Uncertain significance ★★ ⚠ same residue
FARS2 p.Arg330Ser 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-arg330cys (accessed [today's date]).

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