LEPR p.Leu538=
c.1612C>T · rs1038198266 · VCV3031530
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0217%, amr)
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 0.42 | GERP -1.1, phastCons 0.051 |
| Overall | ||
| CADD | 5.648 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0217%
Admixed American · 13/59,978 alleles
Filtering AF
0.0128%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0101%
Overall
0.00124%
20/1,613,310 alleles · ultra-rare
exomes 9/1,461,166 · genomes 11/152,144 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0217% | 4,614 |
| Remaining individualsnot grpmax-eligible | 0.00641% | 15,611 |
| African / African-American | 0.00267% | 37,443 |
| European (non-Finnish) | 8.48e-05% | 1,179,710 |
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
- LEPR
- Protein
- p.Leu538=
- Coding
- c.1612C>T
- MANE Select
- NM_002303
- dbSNP
- rs1038198266
- Type
- single nucleotide variant
- Location
- chr1:65608761 (GRCh38)
- Gene constraint
- LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 66.49 · 9 PDB
- Residue 538
- an α-helix
Similar variants
- LEPR c.995-2A>G Likely pathogenic ★★ same type
- LEPR p.Trp31Ter Pathogenic ★★ same type
- LEPR p.Ala545= Uncertain significance ★★ same type
- LEPR p.Arg678Ser Uncertain significance ★★ ⚠ same type
- LEPR p.Asn397Lys Uncertain significance ★★ ⚠ same type
- LEPR p.Glu565Asp Uncertain significance ★★ ⚠ same type
- LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same type
- LEPR p.Ile551Asn 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/lepr-p-leu538 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown