# NM_002303.6(LEPR):c.1635A>G (p.Ala545=)

https://sugi.bio/variant/lepr-p-ala545

## Summary

**LEPR p.Ala545= (c.1635A>G)** is classified **Uncertain significance** in LEPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-12). Ultra-rare (popmax 0.0165%, mid); Associated with obesity due to leptin receptor gene deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs199507516 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the LEPR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to obesity due to leptin receptor gene deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017083/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LEPR](https://sugi.bio/atlas/gene/LEPR/) |
| Protein change (HGVS p.) | p.Ala545= |
| Coding change (HGVS c.) | c.1635A>G |
| MANE Select transcript | [NM_002303](https://www.ncbi.nlm.nih.gov/nuccore/NM_002303) |
| dbSNP | [rs199507516](https://www.ncbi.nlm.nih.gov/snp/rs199507516/) |
| Variant type | single nucleotide variant |
| Location | chr1:65608784-65608784 (GRCh38) |
| ClinVar | [VCV874953](https://www.ncbi.nlm.nih.gov/clinvar/variation/874953/) |

**All HGVS expressions:** `LRG_283:g.193220A>G`, `LRG_283t1:c.1635A>G`, `LRG_283t2:c.1635A>G`, `LRG_283t3:c.1635A>G`, `LRG_283t4:c.1635A>G`, `NC_000001.10:g.66074467A>G`, `NC_000001.11:g.65608784A>G`, `NG_015831.2:g.193220A>G`, `NM_001003679.3:c.1635A>G`, `NM_001003680.3:c.1635A>G`, `NM_001198687.2:c.1635A>G`, `NM_001198688.1:c.1635A>G`, `NM_001198689.2:c.1635A>G`, `NM_002303.6:c.1635A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.116, GERP 0.258, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.96**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000429% · FAF99 0.000313% · 1/6,072 in the highest group · 91/1,613,670 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.226% | 442 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,805 |
| Middle Eastern (grpmax) | 0.0165% | 6,072 |
| European (non-Finnish) | 0.000848% | 117,984 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**LEPR** population constraint: LOEUF 0.589, pLI 9.3179e-05, missense-Z 2.0667; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **545** lies in the fibronectin type-iii 2 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 66.49, 22% of residues very-high.

**9 experimental structure(s)** (PDB): [3V6O](https://www.rcsb.org/structure/3V6O), [6E2P](https://www.rcsb.org/structure/6E2P), [7Z3Q](https://www.rcsb.org/structure/7Z3Q), [8AVE](https://www.rcsb.org/structure/8AVE), [8AVF](https://www.rcsb.org/structure/8AVF), [8AVO](https://www.rcsb.org/structure/8AVO).

## What this gene does {#gene-function}

*Describes the biological roles of LEPR (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** LEPR's established molecular role includes peptide hormone binding. p.Ala545= falls in the fibronectin type-iii 2 domain.


### Pathways affected {#pathways}

LEPR participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by Leptin](https://reactome.org/content/detail/R-HSA-2586552) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** peptide hormone binding, leptin receptor activity, identical protein binding.

**Biological process:** angiogenesis, negative regulation of autophagy, leptin-mediated signaling pathway, regulation of transport, cell surface receptor signaling pathway via STAT.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-01-12.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2018–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-22 |

## Associated conditions {#conditions}

[obesity due to leptin receptor gene deficiency](https://sugi.bio/atlas/disease/obesity-due-to-leptin-receptor-gene-deficiency/).

**Reported phenotype names (ClinVar):** Obesity due to leptin receptor gene deficiency, LEPR-related disorder, not provided, none provided, LEPR-related disorders, LEPR-related condition.

## Similar variants {#similar}

Related LEPR variant pages (same residue, condition, or type): [LEPR p.Leu471Ile](/variant/lepr-p-leu471ile), [LEPR p.Lys204Arg](/variant/lepr-p-lys204arg), [LEPR p.Pro231Ser](/variant/lepr-p-pro231ser), [LEPR c.2597+15G>C](/variant/lepr-c-2597-plus-15g-c), [LEPR c.370+16G>T](/variant/lepr-c-370-plus-16g-t), [LEPR c.*232G>A](/variant/lepr-c-star-232g-a), [LEPR p.Lys109Arg](/variant/lepr-p-lys109arg), [LEPR p.Pro1019=](/variant/lepr-p-pro1019).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 874953). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*