Is LEPR p.Ile340Val (c.1018A>G) pathogenic?

LEPR p.Ile340Val (c.1018A>G) is classified Conflicting classifications of pathogenicity in LEPR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.0317%, amr); Associated with obesity due to leptin receptor gene deficiency.

What condition is associated with LEPR p.Ile340Val (c.1018A>G)?

LEPR p.Ile340Val (c.1018A>G) is associated with obesity due to leptin receptor gene deficiency (ClinVar).

How common is LEPR p.Ile340Val (c.1018A>G) in the general population?

LEPR p.Ile340Val (c.1018A>G) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about LEPR p.Ile340Val (c.1018A>G)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

LEPR p.Ile340Val

c.1018A>G · rs753573139 · VCV874014

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

obesity due to leptin receptor gene deficiency

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -5.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	18.91	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,974 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00136% 22/1,613,130 alleles · ultra-rare exomes 19/1,461,062 · genomes 3/152,068 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,157
Remaining individualsnot grpmax-eligible	0.0032%	31,224
South Asian	0.0011%	91,066

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.Ile340Val
Coding: c.1018A>G
MANE Select: NM_002303
dbSNP: rs753573139
Type: single nucleotide variant
Location: chr1:65601415 (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 340: the ig-like domain

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.Ile340= Likely benign 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
LEPR c.*232G>A Likely 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-ile340val (accessed [today's date]).

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