Is LEPR p.Pro481Leu (c.1442C>T) pathogenic?

LEPR p.Pro481Leu (c.1442C>T) is classified Uncertain significance in LEPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1029); Very rare (popmax 0.00178%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LEPR p.Pro481Leu (c.1442C>T)?

LEPR p.Pro481Leu (c.1442C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEPR p.Pro481Leu (c.1442C>T) in the general population?

LEPR p.Pro481Leu (c.1442C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about LEPR p.Pro481Leu (c.1442C>T)?

AlphaMissense predicts likely benign (score 0.1029) — an in-silico prediction, not a clinical call.

LEPR p.Pro481Leu

c.1442C>T · rs367797193 · VCV2636021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1029 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1029	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.66, phastCons 0.1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	15.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,006 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00136% 22/1,613,752 alleles · very rare exomes 19/1,461,646 · genomes 3/152,106 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,191
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Pro481Leu
Coding: c.1442C>T
MANE Select: NM_002303
dbSNP: rs367797193
Type: single nucleotide variant
Location: chr1:65605076 (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 481: the 'leptin-binding' region

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.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-pro481leu (accessed [today's date]).

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