Is LEPR p.Ala458= (c.1374G>A) pathogenic?

LEPR p.Ala458= (c.1374G>A) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-12). Very rare (popmax 0.00892%, eas); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Ala458= (c.1374G>A)?

LEPR p.Ala458= (c.1374G>A) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Ala458= (c.1374G>A) in the general population?

LEPR p.Ala458= (c.1374G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

LEPR p.Ala458=

c.1374G>A · rs768308728 · VCV874951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, 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 1.9	GERP 0.58, phastCons 0.96
Overall
CADD	9.038	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,830 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00198% 32/1,613,520 alleles · very rare exomes 28/1,461,434 · genomes 4/152,086 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,207
Finnishnot grpmax-eligible	0.00781%	12,797
African / African-American	0.004%	24,997
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00153%	65,534
South Asian	0.0011%	91,072

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.Ala458=
Coding: c.1374G>A
MANE Select: NM_002303
dbSNP: rs768308728
Type: single nucleotide variant
Location: chr1:65601931 (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.Ala458Val Likely benign ★★ same residue
LEPR p.Ala458Glu 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

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-ala458 (accessed [today's date]).

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