Is TANGO2 p.Arg180Pro (c.539G>C) pathogenic?

TANGO2 p.Arg180Pro (c.539G>C) is classified Uncertain significance in TANGO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-15). AlphaMissense: likely pathogenic (0.5645); Ultra-rare (popmax 0.0129%, amr); Associated with Inborn genetic diseases.

What condition is associated with TANGO2 p.Arg180Pro (c.539G>C)?

TANGO2 p.Arg180Pro (c.539G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TANGO2 p.Arg180Pro (c.539G>C) in the general population?

TANGO2 p.Arg180Pro (c.539G>C) is ultra-rare (popmax 0.0129%, amr) (gnomAD).

What do computational predictors say about TANGO2 p.Arg180Pro (c.539G>C)?

AlphaMissense predicts likely pathogenic (score 0.5645) — an in-silico prediction, not a clinical call.

TANGO2 p.Arg180Pro

c.539G>C · rs914146516 · VCV2172488

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5645	likely pathogenic
REVEL	0.115	moderately benign-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69	GERP -2.8
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	17.96	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 0.0129% Admixed American · 7/54,176 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00424%

Overall 0.000507% 8/1,577,582 alleles · ultra-rare exomes 2/1,425,318 · genomes 6/152,264 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0129%	7,739
African / African-American	0.00134%	74,544

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.Arg180Pro
Coding: c.539G>C
MANE Select: NM_152906
dbSNP: rs914146516
Type: single nucleotide variant
Location: chr22:20061617 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 180: a UniProt-annotated variant site (in mecrcn); a UniProt-annotated variant site (in mecrcn; delayed er-to-golgi transport; altered mitochondrial morphology); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TANGO2 p.Arg180Trp Uncertain significance ★★ ⚠ same residue
TANGO2 p.Arg180Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TANGO2 c.451+2T>A Pathogenic/Likely pathogenic ★★ same condition
TANGO2 p.Ala183Val Uncertain significance ★★ ⚠ same condition
TANGO2 p.Ala246Val Uncertain significance ★★ ⚠ same condition
TANGO2 p.Arg11Cys Uncertain significance ★★ ⚠ same condition
TANGO2 p.Arg230Cys Uncertain significance ★★ ⚠ same condition
TANGO2 p.Arg230His Uncertain significance ★★ ⚠ 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-arg180pro (accessed [today's date]).

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