Is LEPR p.Leu174= (c.522G>A) pathogenic?

LEPR p.Leu174= (c.522G>A) is classified Likely benign in LEPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-15). Ultra-rare (popmax 0.033%, mid); Associated with LEPR-related disorder.

What condition is associated with LEPR p.Leu174= (c.522G>A)?

LEPR p.Leu174= (c.522G>A) is associated with LEPR-related disorder (ClinVar).

How common is LEPR p.Leu174= (c.522G>A) in the general population?

LEPR p.Leu174= (c.522G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

LEPR p.Leu174=

c.522G>A · VCV3358491

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

LEPR-related disorder

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 1.6	GERP 1, phastCons 0.004
Overall
CADD	0.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,052 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000744% 12/1,612,980 alleles · ultra-rare exomes 12/1,461,086 · genomes 0/151,894 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,026
Finnishnot grpmax-eligible	0.00469%	21,319
European (non-Finnish)	0.000594%	168,475

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.Leu174=
Coding: c.522G>A
MANE Select: NM_002303
Type: single nucleotide variant
Location: chr1:65592684 (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

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-leu174 (accessed [today's date]).

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