TSPEAR p.Pro522=
c.1566G>A · rs151318000 · VCV1810688
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.02%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.46 | donor loss · deltas |
|---|---|---|
| Pangolin | Δ0.49 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 3.8 | GERP 1.7, phastCons 1 |
| Overall | ||
| CADD | 20.3 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.02%
African / African-American · 15/74,994 alleles
Filtering AF
0.0123%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00988%
Overall
0.00818%
132/1,613,014 alleles · ultra-rare
exomes 114/1,460,850 · genomes 18/152,164 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.02% | 5,000 |
| Remaining individualsnot grpmax-eligible | 0.016% | 6,246 |
| East Asian | 0.0156% | 6,408 |
| European (non-Finnish) | 0.00814% | 12,288 |
| Admixed American | 0.005% | 19,997 |
| South Asian | 0.0011% | 91,046 |
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
- TSPEAR
- Protein
- p.Pro522=
- Coding
- c.1566G>A
- MANE Select
- NM_144991
- dbSNP
- rs151318000
- Type
- single nucleotide variant
- Location
- chr21:44521883 (GRCh38)
- Gene constraint
- LOEUF 1.161 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 87.47
- Residue 522
- a UniProt-annotated variant site (in ectd14 and sthag10); a UniProt-annotated variant site (in ectd14); a UniProt-annotated variant site (in sthag10)
Similar variants
- TSPEAR p.Pro522Leu Likely benign ★ same residue
- TSPEAR c.1336+2T>A Pathogenic/Likely pathogenic ★★ same type
- TSPEAR c.1337-2A>G Likely pathogenic ★★ same type
- TSPEAR c.1856+2T>C Pathogenic/Likely pathogenic ★★ same type
- TSPEAR p.Arg144Ter Pathogenic ★★ same type
- TSPEAR p.Arg197Ter Pathogenic/Likely pathogenic ★★ same type
- TSPEAR p.Gln365Ter Pathogenic ★★ same type
- TSPEAR p.Gln79Ter Pathogenic/Likely 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/tspear-p-pro522 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown