Is LEPR p.Ser1008= (c.3024A>G) pathogenic?

LEPR p.Ser1008= (c.3024A>G) is classified Benign/Likely benign in LEPR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-31). Common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele; Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Ser1008= (c.3024A>G)?

LEPR p.Ser1008= (c.3024A>G) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

LEPR p.Ser1008=

Q: How common is LEPR p.Ser1008= (c.3024A>G) in the general population?

LEPR p.Ser1008= (c.3024A>G) is common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3024A>G · rs6413506 · VCV791797

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

obesity due to leptin receptor gene deficiency

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 -0.49	GERP -3.6
Overall
CADD	4.097	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.48% African / African-American · 4,109/75,042 alleles

Filtering AF 5.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.28%

Overall 0.287% 4,634/1,614,090 alleles · common exomes 2,338/1,461,782 · genomes 2,296/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.48%	18
Remaining individualsnot grpmax-eligible	0.392%	255
Admixed American	0.325%	308
Middle Eastern	0.115%	866
South Asian	0.0187%	5,358
European (non-Finnish)	0.00508%	19,667
Finnishnot grpmax-eligible	0.00156%	64,034

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.Ser1008=
Coding: c.3024A>G
MANE Select: NM_002303
dbSNP: rs6413506
Type: single nucleotide variant
Location: chr1:65636541 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.49 · 9 PDB

Full LEPR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

obesity due to leptin receptor gene deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEPR p.Ala545= Uncertain significance ★★ same condition
LEPR p.Leu471Ile Uncertain significance ★★ ⚠ same condition
LEPR p.Lys204Arg Uncertain significance ★★ ⚠ same condition
LEPR p.Pro231Ser Uncertain significance ★★ ⚠ same condition
LEPR c.2597+15G>C Benign/Likely benign ★★ same condition
LEPR c.370+16G>T Benign ★★ same condition
LEPR c.*232G>A Likely benign ★★ same condition
LEPR p.Lys109Arg Benign ★★ same condition

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-ser1008 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown