Is TANGO2 p.Thr74Pro (c.220A>C) pathogenic?

TANGO2 p.Thr74Pro (c.220A>C) is classified Uncertain significance in TANGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely pathogenic (0.9152); Absent from gnomAD v4.1; Associated with recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome.

How common is TANGO2 p.Thr74Pro (c.220A>C) in the general population?

TANGO2 p.Thr74Pro (c.220A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TANGO2 p.Thr74Pro (c.220A>C)?

AlphaMissense predicts likely pathogenic (score 0.9152) — an in-silico prediction, not a clinical call.

TANGO2 p.Thr74Pro

Q: What condition is associated with TANGO2 p.Thr74Pro (c.220A>C)?

TANGO2 p.Thr74Pro (c.220A>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.220A>C · rs1235314092 · VCV3064884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9152 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9152	likely pathogenic
REVEL	0.682	pathogenic-leaning
SaProt	LLR -14.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: TANGO2
Protein: p.Thr74Pro
Coding: c.220A>C
MANE Select: NM_152906
dbSNP: rs1235314092
Type: single nucleotide variant
Location: chr22:20052539 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 74: a UniProt-annotated variant site (in mecrcn); a UniProt-annotated variant site (in mecrcn; uncertain significance); 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.Thr74= 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
TANGO2 p.Arg88Ter 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-thr74pro (accessed [today's date]).

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