Is FARS2 p.Asp142Tyr (c.424G>T) pathogenic?

FARS2 p.Asp142Tyr (c.424G>T) is classified Pathogenic in FARS2 (ClinVar, Single submitter, 3 submitters; last evaluated 2018-06-13). AlphaMissense: likely pathogenic (0.6133); Very rare (popmax 0.00223%, eas); Associated with hereditary spastic paraplegia 77.

What condition is associated with FARS2 p.Asp142Tyr (c.424G>T)?

FARS2 p.Asp142Tyr (c.424G>T) is associated with hereditary spastic paraplegia 77 (ClinVar).

How common is FARS2 p.Asp142Tyr (c.424G>T) in the general population?

FARS2 p.Asp142Tyr (c.424G>T) is very rare (popmax 0.00223%, eas) (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.Asp142Tyr (c.424G>T)?

AlphaMissense predicts likely pathogenic (score 0.6133) — an in-silico prediction, not a clinical call.

FARS2 p.Asp142Tyr

c.424G>T · rs145555213 · VCV253159

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 77

Computational evidence

Protein change
AlphaMissense	0.6133	likely pathogenic ✓ concordant with ClinVar
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -13.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.64, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	29.2	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 0.00223% East Asian · 1/44,882 alleles

Overall 6.2e-05% 1/1,614,168 alleles · very rare exomes 1/1,461,888 · genomes 0/152,280 · 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.Asp142Tyr
Coding: c.424G>T
MANE Select: NM_006567
dbSNP: rs145555213
Type: single nucleotide variant
Location: chr6:5368994 (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 142: a UniProt-annotated variant site (in spg77; resulted in severely impaired phenylalanine-trna ligase activity); a turn

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

For Autosomal recessive spastic paraplegia type 77 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

FARS2 p.Asp142Asn Likely pathogenic ★ ⚠ same residue
FARS2 p.Asp142Gly Likely pathogenic ★ same residue
FARS2 p.Asp142Glu Uncertain significance ★ same residue
FARS2 p.Arg419Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
FARS2 p.Arg419His Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Pro361Leu Pathogenic/Likely pathogenic ★★ same condition
FARS2 p.Arg330Cys Uncertain significance ★★ ⚠ same condition
FARS2 p.Asp184Asn Uncertain significance ★★ ⚠ 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-asp142tyr (accessed [today's date]).

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