Is TANGO2 p.Ile4Phe (c.10A>T) pathogenic?

TANGO2 p.Ile4Phe (c.10A>T) is classified Uncertain significance in TANGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.7316); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TANGO2 p.Ile4Phe (c.10A>T)?

TANGO2 p.Ile4Phe (c.10A>T) is associated with Inborn genetic diseases (ClinVar).

How common is TANGO2 p.Ile4Phe (c.10A>T) in the general population?

TANGO2 p.Ile4Phe (c.10A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TANGO2 p.Ile4Phe (c.10A>T)?

AlphaMissense predicts likely pathogenic (score 0.7316) — an in-silico prediction, not a clinical call.

TANGO2 p.Ile4Phe

c.10A>T · VCV3324365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7316	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -13.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 28 kb · p 0.072 · regional, not allelic
Overall
CADD	25.1	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,194 alleles · very rare exomes 3/1,461,892 · genomes 0/152,302 · 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.Ile4Phe
Coding: c.10A>T
MANE Select: NM_152906
Type: single nucleotide variant
Location: chr22:20036808 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 3 PDB
Residue 4: 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.Ile4Asn Uncertain significance ★★ ⚠ same residue
TANGO2 p.Ile4Leu 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-ile4phe (accessed [today's date]).

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