Is VARS2 p.Ser280fs (c.839_843del) pathogenic?

VARS2 p.Ser280fs (c.839843del) is classified Likely pathogenic in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). Associated with combined oxidative phosphorylation defect type 20.

What condition is associated with VARS2 p.Ser280fs (c.839_843del)?

VARS2 p.Ser280fs (c.839_843del) is associated with combined oxidative phosphorylation defect type 20 (ClinVar).

VARS2 p.Ser280fs

Q: How is Combined oxidative phosphorylation defect type 20 inherited?

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

c.839_843del · VCV4845796

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

combined oxidative phosphorylation defect type 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: VARS2
Protein: p.Ser280fs
Coding: c.839_843del
MANE Select: NM_006295 · reported on NM_020442
Type: Deletion
Location: chr6:30917188 (GRCh38)
Structure: AlphaFold pLDDT 88.12
Residue 280: the 'disordered' region

Full VARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 20 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

VARS2 p.Tyr84fs Likely pathogenic ★★ same condition
VARS2 p.Gly450fs Likely pathogenic ★ same condition
VARS2 p.Gly488del Likely pathogenic ★ same condition
VARS2 p.Met141fs Pathogenic ★ same condition
VARS2 p.Phe481fs Pathogenic ★ same condition
VARS2 c.-18_-12del Conflicting classifications of pathogenicity ★ same condition
VARS2 c.1480-2A>G Likely pathogenic ★★ same condition
VARS2 c.2467-2A>G 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/vars2-p-ser280fs (accessed [today's date]).

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