Is LEPR p.Phe500= (c.1500C>T) pathogenic?

LEPR p.Phe500= (c.1500C>T) is classified Likely benign in LEPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-05-08). Absent from gnomAD v4.1; Associated with LEPR-related disorder.

What condition is associated with LEPR p.Phe500= (c.1500C>T)?

LEPR p.Phe500= (c.1500C>T) is associated with LEPR-related disorder (ClinVar).

How common is LEPR p.Phe500= (c.1500C>T) in the general population?

LEPR p.Phe500= (c.1500C>T) is absent from gnomAD v4.1 (gnomAD).

LEPR p.Phe500=

c.1500C>T · VCV3356817

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

LEPR-related disorder

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 1.1	GERP -2.8, phastCons 1
Overall
CADD	6.841	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LEPR
Protein: p.Phe500=
Coding: c.1500C>T
MANE Select: NM_002303
Type: single nucleotide variant
Location: chr1:65605134 (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 500: a β-strand

Full LEPR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

LEPR-related disorder

Similar variants

LEPR c.2213-2A>G Likely pathogenic ★ same condition
LEPR p.Pro316Thr Likely pathogenic ★ ⚠ same condition
LEPR p.Thr661Ala Likely pathogenic ★ ⚠ same condition
LEPR p.Trp664Arg Pathogenic ★ same condition
LEPR p.Ala458Glu Uncertain significance ★ ⚠ same condition
LEPR p.Gln177= Uncertain significance ★ same condition
LEPR p.Gly179Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
LEPR p.Met1160Val Uncertain significance ★ ⚠ 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-phe500 (accessed [today's date]).

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