Is LEPR p.Ser790= (c.2370A>C) pathogenic?

LEPR p.Ser790= (c.2370A>C) is classified Conflicting classifications of pathogenicity in LEPR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-21). Rare (popmax 0.966%, eas); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Ser790= (c.2370A>C)?

LEPR p.Ser790= (c.2370A>C) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Ser790= (c.2370A>C) in the general population?

LEPR p.Ser790= (c.2370A>C) is rare (popmax 0.966%, eas) (gnomAD).

LEPR p.Ser790=

c.2370A>C · rs13306528 · VCV730209

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.966%, eas)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.2	GERP -3.5
Overall
CADD	3.768	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.966% East Asian · 432/44,720 alleles

Filtering AF 0.891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.861%

Overall 0.0272% 438/1,609,588 alleles · rare exomes 406/1,457,292 · genomes 32/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.966%	104
Remaining individualsnot grpmax-eligible	0.00963%	10,379

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.Ser790=
Coding: c.2370A>C
MANE Select: NM_002303
dbSNP: rs13306528
Type: single nucleotide variant
Location: chr1:65618121 (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 790: the fibronectin type-iii 4 domain

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-ser790 (accessed [today's date]).

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