Is LEPR p.Ile366Phe (c.1096A>T) pathogenic?

LEPR p.Ile366Phe (c.1096A>T) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.2862); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LEPR p.Ile366Phe (c.1096A>T)?

LEPR p.Ile366Phe (c.1096A>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEPR p.Ile366Phe (c.1096A>T) in the general population?

LEPR p.Ile366Phe (c.1096A>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about LEPR p.Ile366Phe (c.1096A>T)?

AlphaMissense predicts likely benign (score 0.2862) — an in-silico prediction, not a clinical call.

LEPR p.Ile366Phe

c.1096A>T · rs760913071 · VCV2611027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2862	likely benign
REVEL	0.742	pathogenic-leaning
SaProt	LLR -9.77	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	25.1	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 0.000339% European (non-Finnish) · 4/1,179,736 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,568 alleles · very rare exomes 3/1,461,544 · genomes 1/152,024 · joint denominator

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.Ile366Phe
Coding: c.1096A>T
MANE Select: NM_002303
dbSNP: rs760913071
Type: single nucleotide variant
Location: chr1:65601493 (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 366: the ig-like domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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LEPR p.Glu565Asp Uncertain significance ★★ ⚠ same condition
LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same condition
LEPR p.Ile551Asn Uncertain significance ★★ ⚠ same condition
LEPR p.Leu471Ile Uncertain significance ★★ ⚠ same condition
LEPR p.Pro1068Arg Uncertain significance ★★ ⚠ same condition
LEPR p.Pro231Ser 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-ile366phe (accessed [today's date]).

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