LEPR p.Ser595=
c.1785T>G · rs1403870461 · VCV435749
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00329%, sas)
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 -5.3 | GERP -3.3 |
| Overall | ||
| CADD | 0.086 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00329%
South Asian · 3/91,088 alleles
Filtering AF
0.000875%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000443%
Overall
0.000248%
4/1,614,200 alleles · very rare
exomes 4/1,461,828 · genomes 0/152,372 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00329% | 30,363 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,510 |
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.Ser595=
- Coding
- c.1785T>G
- MANE Select
- NM_002303
- dbSNP
- rs1403870461
- Type
- single nucleotide variant
- Location
- chr1:65609979 (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 595
- the fibronectin type-iii 2 domain; a β-strand
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-ser595 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown