Is LEPR p.Asn682= (c.2046C>T) pathogenic?

LEPR p.Asn682= (c.2046C>T) is classified Conflicting classifications of pathogenicity in LEPR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-30). Ultra-rare (popmax 0.0646%, eas); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Asn682= (c.2046C>T)?

LEPR p.Asn682= (c.2046C>T) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Asn682= (c.2046C>T) in the general population?

LEPR p.Asn682= (c.2046C>T) is ultra-rare (popmax 0.0646%, eas) (gnomAD).

LEPR p.Asn682=

c.2046C>T · rs192825082 · VCV874955

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0646%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP -1.4, phastCons 0.004
Overall
CADD	0.813	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0646% East Asian · 29/44,872 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00285% 46/1,614,114 alleles · ultra-rare exomes 43/1,461,834 · genomes 3/152,280 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0646%	1,547
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.004%	25,015
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,179,993

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.Asn682=
Coding: c.2046C>T
MANE Select: NM_002303
dbSNP: rs192825082
Type: single nucleotide variant
Location: chr1:65616058 (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 682: the fibronectin type-iii 3 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.Asn682Ser Uncertain significance ⚠ same residue
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

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-asn682 (accessed [today's date]).

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