TPP1 p.Arg418=
c.1254G>A · rs1201568521 · VCV1110272
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00267%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.27 | GERP -2.2, phastCons 0.011 |
| Overall | ||
| CADD | 7.505 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00267%
African / African-American · 2/74,916 alleles
Filtering AF
0.00114%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00097%
Overall
0.00149%
24/1,614,086 alleles · very rare
exomes 23/1,461,890 · genomes 1/152,196 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00267% | 37,458 |
| European (non-Finnish) | 0.00178% | 56,193 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,486 |
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
- TPP1
- Protein
- p.Arg418=
- Coding
- c.1254G>A
- MANE Select
- NM_000391
- dbSNP
- rs1201568521
- Type
- single nucleotide variant
- Location
- chr11:6615454 (GRCh38)
- Gene constraint
- LOEUF 0.78 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 90.70 · 2 PDB
- Residue 418
- the peptidase s53 domain
Similar variants
- TPP1 p.Arg418Trp Uncertain significance ★★ ⚠ same residue
- TPP1 p.Arg418Gln Benign/Likely benign ★★ ⚠ same residue
- TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same type
- TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same type
- TPP1 c.1076-2A>T Pathogenic ★★ same type
- TPP1 c.1146-1G>A Likely pathogenic ★★ same type
- TPP1 c.1425+1G>A Likely pathogenic ★★ same type
- TPP1 c.1551+1G>A 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/tpp1-p-arg418 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown