Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 7 submitters
gnomAD v4.1
Common
common (popmax 33.8%, sas) — too common for a highly-penetrant pathogenic allele
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 -2.1 | GERP -3.5 |
| Overall | ||
| CADD | 5.802 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
33.8%
South Asian · 30,786/91,042 alleles
Filtering AF
33.5%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 33.4%
Overall
21.1%
340,656/1,612,898 alleles · common
exomes 304,579/1,460,960 · genomes 36,077/151,938 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 33.8% | 3 |
| African / African-American | 33.1% | 3 |
| Ashkenazi Jewishnot grpmax-eligible | 30.2% | 3 |
| Finnishnot grpmax-eligible | 22.5% | 4 |
| Remaining individualsnot grpmax-eligible | 22% | 5 |
| Middle Eastern | 20.7% | 5 |
| European (non-Finnish) | 19.9% | 5 |
| Admixed American | 14.3% | 7 |
| Amishnot grpmax-eligible | 10.9% | 9 |
| East Asian | 8.33% | 12 |
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.Ser343=
- Coding
- c.1029T>C
- MANE Select
- NM_002303
- dbSNP
- rs1805134
- Type
- single nucleotide variant
- Location
- chr1:65601426 (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 343
- the ig-like domain
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-ser343 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown