Is LEPR p.Pro876= (c.2628G>A) pathogenic?

LEPR p.Pro876= (c.2628G>A) is classified Likely benign in LEPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-06-08). Very rare (popmax 0.00329%, sas); Associated with LEPR-related disorder.

What condition is associated with LEPR p.Pro876= (c.2628G>A)?

LEPR p.Pro876= (c.2628G>A) is associated with LEPR-related disorder (ClinVar).

How common is LEPR p.Pro876= (c.2628G>A) in the general population?

LEPR p.Pro876= (c.2628G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

LEPR p.Pro876=

c.2628G>A · rs748857078 · VCV3029200

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

LEPR-related disorder

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
Pangolin	Δ0.27	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -3, phastCons 1
Overall
CADD	7.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,070 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00105% 17/1,613,758 alleles · very rare exomes 16/1,461,700 · genomes 1/152,058 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,357
Admixed American	0.00167%	59,970
European (non-Finnish)	0.0011%	90,763

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.Pro876=
Coding: c.2628G>A
MANE Select: NM_002303
dbSNP: rs748857078
Type: single nucleotide variant
Location: chr1:65622936 (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

LEPR-related disorder

Similar variants

LEPR c.2213-2A>G Likely pathogenic ★ same condition
LEPR p.Pro316Thr Likely pathogenic ★ ⚠ same condition
LEPR p.Thr661Ala Likely pathogenic ★ ⚠ same condition
LEPR p.Trp664Arg Pathogenic ★ same condition
LEPR p.Ala458Glu Uncertain significance ★ ⚠ same condition
LEPR p.Gln177= Uncertain significance ★ same condition
LEPR p.Gly179Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
LEPR p.Met1160Val 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-pro876 (accessed [today's date]).

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