Is LEPR p.Ala545= (c.1635A>G) pathogenic?

LEPR p.Ala545= (c.1635A>G) is classified Uncertain significance in LEPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-12). Ultra-rare (popmax 0.0165%, mid); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Ala545= (c.1635A>G)?

LEPR p.Ala545= (c.1635A>G) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Ala545= (c.1635A>G) in the general population?

LEPR p.Ala545= (c.1635A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

LEPR p.Ala545=

c.1635A>G · rs199507516 · VCV874953

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

obesity due to leptin receptor gene deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 4.1	GERP 0.26, phastCons 1
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00564% 91/1,613,670 alleles · ultra-rare exomes 85/1,461,442 · genomes 6/152,228 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.226%	442
Remaining individualsnot grpmax-eligible	0.0208%	4,805
Middle Easterngrpmax	0.0165%	6,072
European (non-Finnish)	0.000848%	117,984

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala545=
Coding: c.1635A>G
MANE Select: NM_002303
dbSNP: rs199507516
Type: single nucleotide variant
Location: chr1:65608784 (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 545: the fibronectin type-iii 2 domain; a β-strand

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.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
LEPR p.Pro1019= 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-ala545 (accessed [today's date]).

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