Is TANGO2 p.Val217Ala (c.650T>C) pathogenic?

TANGO2 p.Val217Ala (c.650T>C) is classified Uncertain significance in TANGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: ambiguous (0.3773); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TANGO2 p.Val217Ala (c.650T>C)?

TANGO2 p.Val217Ala (c.650T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TANGO2 p.Val217Ala (c.650T>C) in the general population?

TANGO2 p.Val217Ala (c.650T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TANGO2 p.Val217Ala (c.650T>C)?

AlphaMissense predicts ambiguous (score 0.3773) — an in-silico prediction, not a clinical call.

TANGO2 p.Val217Ala

c.650T>C · rs1401366067 · VCV2409425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3773	ambiguous
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	21.6	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 0.00167% Admixed American · 1/59,988 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,378 alleles · very rare exomes 5/1,461,210 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
European (non-Finnish)	0.000424%	235,978

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.Val217Ala
Coding: c.650T>C
MANE Select: NM_152906
dbSNP: rs1401366067
Type: single nucleotide variant
Location: chr22:20063382 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 217: 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.Val217Glu Uncertain significance ★ ⚠ same residue
TANGO2 p.Val217Met Uncertain significance ★ ⚠ 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.Arg180Pro Uncertain significance ★★ ⚠ same condition
TANGO2 p.Arg180Trp 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-val217ala (accessed [today's date]).

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