Is FARS2 p.His159Pro (c.476A>C) pathogenic?

FARS2 p.His159Pro (c.476A>C) is classified Conflicting classifications of pathogenicity in FARS2 (ClinVar, Conflicting submitters, 1 submitter; last evaluated 2018-06-13). AlphaMissense: likely pathogenic (0.9132); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 77.

What condition is associated with FARS2 p.His159Pro (c.476A>C)?

FARS2 p.His159Pro (c.476A>C) is associated with hereditary spastic paraplegia 77, combined oxidative phosphorylation defect type 14 (ClinVar).

How common is FARS2 p.His159Pro (c.476A>C) in the general population?

FARS2 p.His159Pro (c.476A>C) is absent from gnomAD v4.1 (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.His159Pro (c.476A>C)?

AlphaMissense predicts likely pathogenic (score 0.9132) — an in-silico prediction, not a clinical call.

FARS2 p.His159Pro

c.476A>C · rs1561990390 · VCV587653

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9132 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 77

Computational evidence

Protein change
AlphaMissense	0.9132	likely pathogenic
REVEL	0.609	indeterminate
SaProt	LLR -15.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 403 kb · p 0.021 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FARS2
Protein: p.His159Pro
Coding: c.476A>C
MANE Select: NM_006567
dbSNP: rs1561990390
Type: single nucleotide variant
Location: chr6:5369046 (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 159: a binding site; 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.His159Gln Uncertain significance ★ ⚠ same residue
FARS2 p.His159Tyr 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-his159pro (accessed [today's date]).

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