# NM_001001548.3(CD36):c.1313_1316dup (p.Leu440fs)

https://sugi.bio/variant/cd36-p-leu440fs

## Summary

**CD36 p.Leu440fs (c.1313_1316dup)** is classified **Likely pathogenic** in CD36 (ClinVar, Single submitter, 1 submitter). Ultra-rare (popmax 0.0179%, eas); Associated with coronary heart disease, susceptibility to, 7.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 3 linked conditions · ultra-rare (popmax 0.0179%, eas)

## For patients & families {#patients}

This is a change in the CD36 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to coronary heart disease, susceptibility to, 7.

*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 | [CD36](https://sugi.bio/atlas/gene/CD36/) |
| Protein change (HGVS p.) | p.Leu440fs |
| Coding change (HGVS c.) | c.1313_1316dup |
| MANE Select transcript | [NM_001001548](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001548) |
| Variant type | Duplication |
| Location | chr7:80674037-80674038 (GRCh38) |
| ClinVar | [VCV3382270](https://www.ncbi.nlm.nih.gov/clinvar/variation/3382270/) |

**All HGVS expressions:** `NC_000007.13:g.80303357_80303360dup`, `NC_000007.14:g.80674041_80674044dup`, `NG_008192.1:g.76854_76857dup`, `NM_000072.3:c.1313_1316dup`, `NM_001001547.3:c.1313_1316dup`, `NM_001001548.3:c.1313_1316dup`, `NM_001127443.2:c.1313_1316dup`, `NM_001127444.2:c.1313_1316dup`, `NM_001289908.1:c.1196_1199dup`, `NM_001289909.1:c.1133_1136dup`, `NM_001289911.2:c.1085_1088dup`, `NM_001371074.1:c.1313_1316dup`, `NM_001371075.1:c.1313_1316dup`, `NM_001371077.1:c.1313_1316dup`, `NM_001371078.1:c.1313_1316dup`, `NM_001371079.1:c.1211_1214dup`, `NM_001371080.1:c.848_851dup`, `NM_001371081.1:c.848_851dup`, `NR_110501.1:n.1304_1307dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.219, GERP 2.04, phastCons 1 — 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 31.0**. 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 duplication 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 **0.0179%** (eas) · FAF95 0.00887% · FAF99 0.00643% · 8/44,696 in the highest group · 8/1,612,346 alleles overall — ultra-rare (popmax 0.0179%, eas).

*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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[coronary heart disease, susceptibility to, 7](https://sugi.bio/atlas/disease/coronary-heart-disease-susceptibility-to-7/), [platelet-type bleeding disorder 10](https://sugi.bio/atlas/disease/platelet-type-bleeding-disorder-10/), [malaria, susceptibility to](https://sugi.bio/atlas/disease/malaria-susceptibility-to/).

**Reported phenotype names (ClinVar):** Coronary heart disease, susceptibility to, 7, Malaria, susceptibility to, Platelet-type bleeding disorder 10, CD36 DEFICIENCY.

## Similar variants {#similar}

Related CD36 variant pages (same residue, condition, or type): [CD36 p.Gln262fs](/variant/cd36-p-gln262fs), [CD36 p.Ile317fs](/variant/cd36-p-ile317fs), [CD36 p.Val411fs](/variant/cd36-p-val411fs), [CD36 p.Ala225fs](/variant/cd36-p-ala225fs), [CD36 p.Glu445fs](/variant/cd36-p-glu445fs), [CD36 p.Val128fs](/variant/cd36-p-val128fs), [CD36 c.1226_1254+4dup](/variant/cd36-c-1226-1254-plus-4dup), [CD36 p.Asn151fs](/variant/cd36-p-asn151fs).

### 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 3382270). 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.*