ERAP1 p.Leu646=
c.1938C>T · rs76598089 · VCV715716
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
low-frequency (popmax 1.24%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.091 | GERP -3.4, phastCons 0.07 |
| Overall | ||
| CADD | 7.182 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.24%
African / African-American · 932/74,992 alleles
Filtering AF
1.18%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.15%
Overall
0.068%
1,098/1,614,026 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 1.24% | 80 |
| Middle Eastern | 0.115% | 866 |
| Remaining individualsnot grpmax-eligible | 0.114% | 880 |
| Admixed American | 0.0866% | 1,154 |
| East Asian | 0.0134% | 7,481 |
| European (non-Finnish) | 0.00254% | 39,331 |
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
- ERAP1
- Protein
- p.Leu646=
- Coding
- c.1938C>T
- MANE Select
- NM_001040458
- dbSNP
- rs76598089
- Type
- single nucleotide variant
- Location
- chr5:96785793 (GRCh38)
- Gene constraint
- LOEUF 0.947 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 92.78 · 27 PDB
- Residue 646
- an α-helix
Similar variants
- ERAP1 p.Ala356= Benign ★★ same type
- ERAP1 p.Gly514Arg Benign/Likely benign ★★ same type
- ERAP1 p.Ile915Thr Likely benign ★★ ⚠ same type
- ERAP1 p.Ser18= Benign/Likely benign ★★ same type
- ERAP1 p.Tyr57= Benign/Likely benign ★★ same type
- ERAP1 p.Tyr789= Benign ★★ same type
- ERAP2 p.Leu411Arg Benign/Likely benign ★★ ⚠ same type
- CAST p.Leu618Phe Uncertain significance ★ ⚠ 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/erap1-p-leu646 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown