# NM_002303.6(LEPR):c.66T>C (p.Phe22=)

https://sugi.bio/variant/lepr-p-phe22

## Summary

**LEPR p.Phe22= (c.66T>C)** is classified **Likely benign** in LEPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-09-11). Very rare (popmax 0.00439%, sas); Associated with LEPR-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the LEPR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to LEPR-related disorder.

*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:** [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.Phe22= |
| Coding change (HGVS c.) | c.66T>C |
| MANE Select transcript | [NM_002303](https://www.ncbi.nlm.nih.gov/nuccore/NM_002303) |
| Variant type | single nucleotide variant |
| Location | chr1:65570498-65570498 (GRCh38) |
| ClinVar | [VCV3350741](https://www.ncbi.nlm.nih.gov/clinvar/variation/3350741/) |

**All HGVS expressions:** `LRG_283:g.154934T>C`, `LRG_283t1:c.66T>C`, `LRG_283t2:c.66T>C`, `LRG_283t3:c.66T>C`, `LRG_283t4:c.66T>C`, `NC_000001.10:g.66036181T>C`, `NC_000001.11:g.65570498T>C`, `NG_015831.2:g.154934T>C`, `NM_001003679.3:c.66T>C`, `NM_001003680.3:c.66T>C`, `NM_001198687.2:c.66T>C`, `NM_001198688.1:c.66T>C`, `NM_001198689.2:c.66T>C`, `NM_002303.6:c.66T>C`

## 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 0.34) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.179, GERP 2.62, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 5.368**. 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 **0.02**, donor loss **0.00**, acceptor gain **0.34**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.34**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,030 in the highest group · 13/1,613,710 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,757 |
| European (non-Finnish) | 0.000763% | 131,104 |

*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}


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.


### 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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-09-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-09-11 |

## Associated conditions {#conditions}

[LEPR-related disorder](https://sugi.bio/atlas/disease/lepr-related-disorder/).

**Reported phenotype names (ClinVar):** LEPR-related disorder, LEPR-related condition, LEPR-related disorders.

## Similar variants {#similar}

Related LEPR variant pages (same residue, condition, or type): [LEPROT p.Met22Thr](/variant/leprot-p-met22thr), [LEPR c.2213-2A>G](/variant/lepr-c-2213-minus-2a-g), [LEPR p.Pro316Thr](/variant/lepr-p-pro316thr), [LEPR p.Thr661Ala](/variant/lepr-p-thr661ala), [LEPR p.Trp664Arg](/variant/lepr-p-trp664arg), [LEPR p.Ala458Glu](/variant/lepr-p-ala458glu), [LEPR p.Gln177=](/variant/lepr-p-gln177), [LEPR p.Gly179Asp](/variant/lepr-p-gly179asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3350741). 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.*