Is LEPR p.Val115= (c.345A>G) pathogenic?

LEPR p.Val115= (c.345A>G) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). Very rare (popmax 0.00839%, nfe); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Val115= (c.345A>G)?

LEPR p.Val115= (c.345A>G) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Val115= (c.345A>G) in the general population?

LEPR p.Val115= (c.345A>G) is very rare (popmax 0.00839%, nfe) (gnomAD).

LEPR p.Val115=

c.345A>G · rs773805917 · VCV875833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00839%, 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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.41	GERP -0.55, phastCons 0.001
Overall
CADD	5.334	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00839% European (non-Finnish) · 97/1,156,324 alleles

Filtering AF 0.00703% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00646%

Overall 0.00633% 99/1,564,802 alleles · very rare exomes 94/1,412,592 · genomes 5/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00839%	11,921
Admixed American	0.00192%	51,996
Remaining individualsnot grpmax-eligible	0.00166%	60,320

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.Val115=
Coding: c.345A>G
MANE Select: NM_002303
dbSNP: rs773805917
Type: single nucleotide variant
Location: chr1:65570777 (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-val115 (accessed [today's date]).

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