# NM_001001548.3(CD36):c.1345_1348del (p.Leu449fs)

https://sugi.bio/variant/cd36-p-leu449fs

## Summary

**CD36 p.Leu449fs (c.1345_1348del)** is classified **Uncertain significance** in CD36 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). Ultra-rare (popmax 0.0329%, mid); Associated with platelet-type bleeding disorder 10.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1261881244 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the CD36 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to platelet-type bleeding disorder 10.

*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/0024837/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD36](https://sugi.bio/atlas/gene/CD36/) |
| Protein change (HGVS p.) | p.Leu449fs |
| Coding change (HGVS c.) | c.1345_1348del |
| MANE Select transcript | [NM_001001548](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001548) |
| dbSNP | [rs1261881244](https://www.ncbi.nlm.nih.gov/snp/rs1261881244/) |
| Variant type | Deletion |
| Location | chr7:80674072-80674075 (GRCh38) |
| ClinVar | [VCV3067875](https://www.ncbi.nlm.nih.gov/clinvar/variation/3067875/) |

**All HGVS expressions:** `NC_000007.13:g.80303389_80303392del`, `NC_000007.14:g.80674073_80674076del`, `NG_008192.1:g.76886_76889del`, `NM_000072.3:c.1345_1348del`, `NM_001001547.3:c.1345_1348del`, `NM_001001548.3:c.1345_1348del`, `NM_001127443.2:c.1345_1348del`, `NM_001127444.2:c.1345_1348del`, `NM_001289908.1:c.1228_1231del`, `NM_001289909.1:c.1165_1168del`, `NM_001289911.2:c.1117_1120del`, `NM_001371074.1:c.1345_1348del`, `NM_001371075.1:c.1345_1348del`, `NM_001371077.1:c.1345_1348del`, `NM_001371078.1:c.1345_1348del`, `NM_001371079.1:c.1243_1246del`, `NM_001371080.1:c.880_883del`, `NM_001371081.1:c.880_883del`, `NR_110501.1:n.1336_1339del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 6.184, GERP 0.832, phastCons 0.98 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.953, pLI 8.8525e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 32.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.00581% · FAF99 0.00242% · 2/6,070 in the highest group · 6/1,610,318 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,035 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,332 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,960 |
| African / African-American | 0.00134% | 74,824 |
| European (non-Finnish) | 8.5e-05% | 1,177,110 |

*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}

**CD36** population constraint: LOEUF 1.953, pLI 8.8525e-17, missense-Z -1.819; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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 94.14, 84% of residues very-high.

**1 experimental structure(s)** (PDB): [5LGD](https://www.rcsb.org/structure/5LGD).

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

*Describes the biological roles of CD36 (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:** CD36's established molecular role includes amyloid-beta binding. In Reactome, CD36 is annotated in disease pathway(s) including **IRAK4 deficiency (TLR2/4)**, **MyD88 deficiency (TLR2/4)**.

**Disease mechanism (Reactome):** CD36 loss or alteration is curated in [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041), [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498).

### Pathways affected {#pathways}

CD36 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041) | curated |
| ⚕ [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498) | curated |
| [Cross-presentation of particulate exogenous antigens (phagosomes)](https://reactome.org/content/detail/R-HSA-1236973) | curated |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Intracellular metabolism of fatty acids regulates insulin secretion](https://reactome.org/content/detail/R-HSA-434313) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of TLR by endogenous ligand](https://reactome.org/content/detail/R-HSA-5686938) | curated |
| [Toll Like Receptor TLR6:TLR2 Cascade](https://reactome.org/content/detail/R-HSA-168188) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [Scavenging by Class B Receptors](https://reactome.org/content/detail/R-HSA-3000471) | electronic |

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

**Molecular function:** amyloid-beta binding, low-density lipoprotein particle receptor activity, scavenger receptor activity, long-chain fatty acid transmembrane transporter activity, lipid binding, short-chain fatty acid transmembrane transporter activity.

**Biological process:** positive regulation of cell-matrix adhesion, receptor-mediated endocytosis, inflammatory response, positive regulation of macrophage derived foam cell differentiation, fatty acid transport, long-chain fatty acid transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-04 |

## Associated conditions {#conditions}

[platelet-type bleeding disorder 10](https://sugi.bio/atlas/disease/platelet-type-bleeding-disorder-10/).

**Reported phenotype names (ClinVar):** Platelet-type bleeding disorder 10, CD36 DEFICIENCY.

## Similar variants {#similar}

Related CD36 variant pages (same residue, condition, or type): [CD36 p.Ile399fs](/variant/cd36-p-ile399fs), [CD36 p.Ile410_Ile413del](/variant/cd36-p-ile410-ile413del), [CD36 p.Lys213fs](/variant/cd36-p-lys213fs), [CD36 p.Lys223fs](/variant/cd36-p-lys223fs), [CD36 c.818+1_818+9del](/variant/cd36-c-818-plus-1-818-plus-9del), [CD36 c.(?_-183](/variant/cd36-c-minus-183), [CD36 p.Gln171fs](/variant/cd36-p-gln171fs), [CD36 p.Lys36fs](/variant/cd36-p-lys36fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3067875). 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.*