Is TANGO2 p.Leu20Pro (c.59T>C) pathogenic?

TANGO2 p.Leu20Pro (c.59T>C) is classified Likely pathogenic in TANGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.9919); Very rare (popmax 8.49e-05%, nfe); Associated with recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome.

How common is TANGO2 p.Leu20Pro (c.59T>C) in the general population?

TANGO2 p.Leu20Pro (c.59T>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about TANGO2 p.Leu20Pro (c.59T>C)?

AlphaMissense predicts likely pathogenic (score 0.9919) — an in-silico prediction, not a clinical call.

TANGO2 p.Leu20Pro

Q: What condition is associated with TANGO2 p.Leu20Pro (c.59T>C)?

TANGO2 p.Leu20Pro (c.59T>C) 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.59T>C · VCV3767164

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9919	likely pathogenic ✓ concordant with ClinVar · top 2% in TANGO2
REVEL	0.636	indeterminate
SaProt	LLR -16.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	29.5	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 8.49e-05% European (non-Finnish) · 1/1,178,226 alleles

Overall 6.2e-05% 1/1,611,662 alleles · very rare exomes 1/1,459,330 · genomes 0/152,332 · 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.Leu20Pro
Coding: c.59T>C
MANE Select: NM_152906
Type: single nucleotide variant
Location: chr22:20043357 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 20: a UniProt-annotated variant site (in mecrcn); a β-strand

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 p.Leu20Arg Uncertain significance ★ ⚠ same residue
TANGO2 p.Leu20= 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
TANGO2 p.Arg140Ter Pathogenic ★★ same condition
TANGO2 p.Arg32Ter Pathogenic/Likely pathogenic ★★ same condition
TANGO2 p.Arg86Ter 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-leu20pro (accessed [today's date]).

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