Is TANGO2 p.Cys231Phe (c.692G>T) pathogenic?

TANGO2 p.Cys231Phe (c.692G>T) is classified Uncertain significance in TANGO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-22). AlphaMissense: likely benign (0.1889); Ultra-rare (popmax 0.0133%, amr); Associated with Acute rhabdomyolysis.

What condition is associated with TANGO2 p.Cys231Phe (c.692G>T)?

TANGO2 p.Cys231Phe (c.692G>T) is associated with Acute rhabdomyolysis (ClinVar).

How common is TANGO2 p.Cys231Phe (c.692G>T) in the general population?

TANGO2 p.Cys231Phe (c.692G>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about TANGO2 p.Cys231Phe (c.692G>T)?

AlphaMissense predicts likely benign (score 0.1889) — an in-silico prediction, not a clinical call.

TANGO2 p.Cys231Phe

c.692G>T · rs149711961 · VCV1377431

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1889 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Acute rhabdomyolysis

Computational evidence

Protein change
AlphaMissense	0.1889	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0133% Admixed American · 8/59,972 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00595% 96/1,612,726 alleles · ultra-rare exomes 85/1,460,480 · genomes 11/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,496
Remaining individualsnot grpmax-eligible	0.00961%	10,406
European (non-Finnish)	0.00695%	14,384

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.Cys231Phe
Coding: c.692G>T
MANE Select: NM_152906
dbSNP: rs149711961
Type: single nucleotide variant
Location: chr22:20063424 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 231: a UniProt-annotated variant site (in mecrcn); a UniProt-annotated variant site (in mecrcn; delayed er-to-golgi transport; altered mitochondrial morphology)

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

Disease context

Acute rhabdomyolysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TANGO2 p.Gly154Arg Pathogenic/Likely pathogenic ★★ same condition
TANGO2 c.146-3605_451+2245del Pathogenic ★ same condition
TANGO2 p.Ile190_Leu197del Likely pathogenic ★ same condition
TANGO2 c.451+2T>A Pathogenic/Likely pathogenic ★★ same type
TANGO2 c.57-1G>C Pathogenic/Likely pathogenic ★★ same type
TANGO2 c.605+1G>A Pathogenic/Likely pathogenic ★★ same type
TANGO2 c.711-3C>G Pathogenic/Likely pathogenic ★★ same type
TANGO2 p.Arg140Ter Pathogenic ★★ same type

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-cys231phe (accessed [today's date]).

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