Is LEPR p.Pro1019= (c.3057G>A) pathogenic?

LEPR p.Pro1019= (c.3057G>A) is classified Benign in LEPR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 86.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Pro1019= (c.3057G>A)?

LEPR p.Pro1019= (c.3057G>A) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

LEPR p.Pro1019=

Q: How common is LEPR p.Pro1019= (c.3057G>A) in the general population?

LEPR p.Pro1019= (c.3057G>A) is common (popmax 86.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3057G>A · rs1805096 · VCV298000

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 86.9%, eas) — 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -3.6
Overall
CADD	0.329	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 86.9% East Asian · 38,963/44,862 alleles

Filtering AF 86.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.8%

Overall 40.6% 655,639/1,613,714 alleles · common exomes 589,205/1,461,754 · genomes 66,434/151,960 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	86.9%	1
Admixed American	49.3%	2
Finnishnot grpmax-eligible	48.2%	2
South Asian	46.4%	2
African / African-American	45.2%	2
Remaining individualsnot grpmax-eligible	41.5%	2
Ashkenazi Jewishnot grpmax-eligible	38.1%	3
European (non-Finnish)	37.3%	3
Middle Eastern	36.1%	3
Amishnot grpmax-eligible	33%	3

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.Pro1019=
Coding: c.3057G>A
MANE Select: NM_002303
dbSNP: rs1805096
Type: single nucleotide variant
Location: chr1:65636574 (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.Pro1019Leu 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-pro1019 (accessed [today's date]).

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