Is VARS2 p.Phe481fs (c.1443del) pathogenic?

VARS2 p.Phe481fs (c.1443del) is classified Pathogenic in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-09). Very rare (popmax 0.00855%, amr); Associated with combined oxidative phosphorylation defect type 20.

What condition is associated with VARS2 p.Phe481fs (c.1443del)?

VARS2 p.Phe481fs (c.1443del) is associated with combined oxidative phosphorylation defect type 20 (ClinVar).

How common is VARS2 p.Phe481fs (c.1443del) in the general population?

VARS2 p.Phe481fs (c.1443del) is very rare (popmax 0.00855%, amr) (gnomAD).

VARS2 p.Phe481fs

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.1443del · VCV4848726

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00855%, amr)

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 2.1, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00855% Admixed American · 5/58,498 alleles

Filtering AF 0.00332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00211%

Overall 0.000414% 6/1,450,144 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00855%	11,700
Remaining individualsnot grpmax-eligible	0.00161%	62,102

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: VARS2
Protein: p.Phe481fs
Coding: c.1443del
MANE Select: NM_020442
Type: Deletion
Location: chr6:30920711 (GRCh38)
Structure: AlphaFold pLDDT 88.12

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.Ser280fs Likely 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-phe481fs (accessed [today's date]).

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