Is LEPR p.Val198= (c.594G>A) pathogenic?

LEPR p.Val198= (c.594G>A) is classified Conflicting classifications of pathogenicity in LEPR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.182%, nfe); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Val198= (c.594G>A)?

LEPR p.Val198= (c.594G>A) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Val198= (c.594G>A) in the general population?

LEPR p.Val198= (c.594G>A) is rare (popmax 0.182%, nfe) (gnomAD).

LEPR p.Val198=

c.594G>A · rs140347630 · VCV875835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.182%, nfe)

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	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.35	GERP 0.048, phastCons 0.97
Overall
CADD	2.709	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.182% European (non-Finnish) · 2,151/1,179,476 alleles

Filtering AF 0.176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.141% 2,269/1,613,278 alleles · rare exomes 2,167/1,461,252 · genomes 102/152,026 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.182%	548
Remaining individualsnot grpmax-eligible	0.0993%	1,007
African / African-American	0.0347%	2,883
Finnishnot grpmax-eligible	0.0297%	3,369
Admixed American	0.0184%	5,447

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.Val198=
Coding: c.594G>A
MANE Select: NM_002303
dbSNP: rs140347630
Type: single nucleotide variant
Location: chr1:65592756 (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.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
LEPR p.Lys109Arg 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-val198 (accessed [today's date]).

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