Is TANGO2 p.His94fs (c.280del) pathogenic?

TANGO2 p.His94fs (c.280del) is classified Pathogenic/Likely pathogenic in TANGO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-30). Very rare (popmax 6.2e-05%); Associated with recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome.

How common is TANGO2 p.His94fs (c.280del) in the general population?

TANGO2 p.His94fs (c.280del) is very rare (popmax 6.2e-05%) (gnomAD).

TANGO2 p.His94fs

Q: What condition is associated with TANGO2 p.His94fs (c.280del)?

TANGO2 p.His94fs (c.280del) is associated with recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (ClinVar).

Q: How is Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome inherited?

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

c.280del · rs2046773175 · VCV1710052

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.24	GERP -2.3, phastCons 0.49

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,612,326 alleles · very rare exomes 1/1,460,088 · genomes 0/152,238 · 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: TANGO2
Protein: p.His94fs
Coding: c.280del
MANE Select: NM_152906
dbSNP: rs2046773175
Type: Deletion
Location: chr22:20053449 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 94: a UniProt-annotated variant site (in mecrcn); an α-helix

Full TANGO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TANGO2 c.57-1743_*10769del Pathogenic ★★ same condition
TANGO2 p.Cys2fs Pathogenic/Likely pathogenic ★★ same condition
TANGO2 c.146-3605_451+2245del Pathogenic ★ same condition
TANGO2 p.Ile190_Leu197del Likely pathogenic ★ same condition
TANGO2 p.His94= Likely benign ★ same residue
TANGO2 c.57-1G>C Pathogenic/Likely pathogenic ★★ same condition
TANGO2 c.605+1G>A Pathogenic/Likely pathogenic ★★ same condition
TANGO2 c.711-3C>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/tango2-p-his94fs (accessed [today's date]).

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