# NM_001001548.3(CD36):c.1181_1185dup (p.Glu397fs)

https://sugi.bio/variant/cd36-p-glu397fs

## Summary

**CD36 p.Glu397fs (c.1181_1185dup)** is classified **Conflicting classifications of pathogenicity** in CD36 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-02-21). Rare (popmax 0.272%, mid); Associated with platelet-type bleeding disorder 10.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs757570230 · 6 submitters · 1 linked condition · rare (popmax 0.272%, mid)

## For patients & families {#patients}

This is a change in the CD36 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, 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.Glu397fs |
| Coding change (HGVS c.) | c.1181_1185dup |
| MANE Select transcript | [NM_001001548](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001548) |
| dbSNP | [rs757570230](https://www.ncbi.nlm.nih.gov/snp/rs757570230/) |
| Variant type | Duplication |
| Location | chr7:80672822-80672823 (GRCh38) |
| ClinVar | [VCV360768](https://www.ncbi.nlm.nih.gov/clinvar/variation/360768/) |

**All HGVS expressions:** `NC_000007.13:g.80302141_80302145dup`, `NC_000007.14:g.80672825_80672829dup`, `NG_008192.1:g.75638_75642dup`, `NM_000072.3:c.1181_1185dup`, `NM_001001547.3:c.1181_1185dup`, `NM_001001548.3:c.1181_1185dup`, `NM_001127443.1:c.1181_1185dup`, `NM_001127443.2:c.1181_1185dup`, `NM_001127444.2:c.1181_1185dup`, `NM_001289908.1:c.1064_1068dup`, `NM_001289909.1:c.1001_1005dup`, `NM_001289911.2:c.953_957dup`, `NM_001371074.1:c.1181_1185dup`, `NM_001371075.1:c.1181_1185dup`, `NM_001371077.1:c.1181_1185dup`, `NM_001371078.1:c.1181_1185dup`, `NM_001371079.1:c.1079_1083dup`, `NM_001371080.1:c.716_720dup`, `NM_001371081.1:c.716_720dup`, `NR_110501.1:n.1172_1176dup`

## 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 4.944, GERP 0.829, 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 12 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 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 **0.272%** (mid) · FAF95 0.171% · FAF99 0.139% · 16/5,880 in the highest group · 118/1,610,522 alleles overall — rare (popmax 0.272%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.272% | 367 |
| Remaining individuals (not grpmax-eligible) | 0.0161% | 6,230 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0102% | 9,844 |
| European (non-Finnish) | 0.00671% | 14,908 |
| South Asian | 0.0066% | 15,155 |
| Admixed American | 0.00334% | 29,920 |
| African / African-American | 0.00267% | 37,451 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-02-21.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Uncertain significance, 1 Pathogenic).

**Submission history:** 6 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-16 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2023-07-11 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-12-04 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-21 |

## 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, not provided, none provided, 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.Leu440fs](/variant/cd36-p-leu440fs), [CD36 p.Val128fs](/variant/cd36-p-val128fs), [CD36 c.1226_1254+4dup](/variant/cd36-c-1226-1254-plus-4dup).

### 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 360768). 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.*