Is TANGO2 p.Arg255Ser (c.763C>A) pathogenic?

TANGO2 p.Arg255Ser (c.763C>A) is classified Uncertain significance in TANGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-02). AlphaMissense: likely pathogenic (0.8861); Very rare (popmax 6.2e-05%).

How common is TANGO2 p.Arg255Ser (c.763C>A) in the general population?

TANGO2 p.Arg255Ser (c.763C>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TANGO2 p.Arg255Ser (c.763C>A)?

AlphaMissense predicts likely pathogenic (score 0.8861) — an in-silico prediction, not a clinical call.

TANGO2 p.Arg255Ser

c.763C>A · rs201237746 · VCV1488046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8861	likely pathogenic
REVEL	0.421	indeterminate
SaProt	LLR -10.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,836 · genomes 0/152,290 · joint denominator

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.Arg255Ser
Coding: c.763C>A
MANE Select: NM_152906
dbSNP: rs201237746
Type: single nucleotide variant
Location: chr22:20064594 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 255: a UniProt-annotated variant site (in mecrcn); a UniProt-annotated variant site (in mecrcn; delayed er-to-golgi transport; altered mitochondrial morphology); 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

Similar variants

TANGO2 p.Arg255Cys Uncertain significance ★★ ⚠ same residue
TANGO2 p.Arg255His Uncertain significance ★★ ⚠ same residue
TANGO2 p.Arg255= Likely benign ★ same residue
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-arg255ser (accessed [today's date]).

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