Is TANGO2 p.Val227Met (c.679G>A) pathogenic?

TANGO2 p.Val227Met (c.679G>A) is classified Uncertain significance in TANGO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.5397); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with TANGO2 p.Val227Met (c.679G>A)?

TANGO2 p.Val227Met (c.679G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TANGO2 p.Val227Met (c.679G>A) in the general population?

TANGO2 p.Val227Met (c.679G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TANGO2 p.Val227Met (c.679G>A)?

AlphaMissense predicts ambiguous (score 0.5397) — an in-silico prediction, not a clinical call.

TANGO2 p.Val227Met

c.679G>A · rs765573865 · VCV2083790

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5397	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -8.27	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 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	26.4	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 0.00133% African / African-American · 1/74,942 alleles

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

Overall 0.000372% 6/1,613,296 alleles · very rare exomes 4/1,461,048 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,942
European (non-Finnish)	0.000424%	235,971

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.Val227Met
Coding: c.679G>A
MANE Select: NM_152906
dbSNP: rs765573865
Type: single nucleotide variant
Location: chr22:20063411 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 227: a UniProt-annotated variant site (in mecrcn); a UniProt-annotated variant site (in mecrcn; delayed er-to-golgi transport; altered mitochondrial morphology); a β-strand

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.Val227= Likely benign ★ 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
TANGO2 p.Arg230Cys 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-val227met (accessed [today's date]).

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