# NM_001001548.3(CD36):c.268C>T (p.Pro90Ser)

https://sugi.bio/variant/cd36-p-pro90ser

## Summary

**CD36 p.Pro90Ser (c.268C>T)** is classified **Conflicting classifications of pathogenicity** in CD36 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9661); Low-frequency (popmax 2.98%, eas); Associated with inherited bleeding disorder, platelet-type.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs75326924 · 9 submitters · 2 linked conditions · AlphaMissense likely pathogenic · low-frequency (popmax 2.98%, eas)

## 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 9 submitters, and is linked to inherited bleeding disorder, platelet-type.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022702/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.Pro90Ser |
| Coding change (HGVS c.) | c.268C>T |
| MANE Select transcript | [NM_001001548](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001548) |
| dbSNP | [rs75326924](https://www.ncbi.nlm.nih.gov/snp/rs75326924/) |
| Variant type | single nucleotide variant |
| Location | chr7:80656687-80656687 (GRCh38) |
| ClinVar | [VCV13535](https://www.ncbi.nlm.nih.gov/clinvar/variation/13535/) |

**All HGVS expressions:** `NC_000007.13:g.80286003C>T`, `NC_000007.14:g.80656687C>T`, `NG_008192.1:g.59500C>T`, `NM_000072.3:c.268C>T`, `NM_001001547.3:c.268C>T`, `NM_001001548.3:c.268C>T`, `NM_001127443.2:c.268C>T`, `NM_001127444.2:c.268C>T`, `NM_001289908.1:c.268C>T`, `NM_001289909.1:c.268C>T`, `NM_001289911.2:c.40C>T`, `NM_001371074.1:c.268C>T`, `NM_001371075.1:c.268C>T`, `NM_001371077.1:c.268C>T`, `NM_001371078.1:c.268C>T`, `NM_001371079.1:c.166C>T`, `NM_001371080.1:c.-184-4376C>T`, `NM_001371081.1:c.-215C>T`, `NR_110501.1:n.447C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9661)
- REVEL 0.944 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.457 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.713, GERP 2.07, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CD36 (of 2,789 modeled).
- CADD: **PHRED 26.7**. 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.*
- Regional missense constraint: **o/e 1.47** across the covering region of the MANE Select transcript (80,646,741–80,674,144), spanning 27,403 bp. Chi-square p 5.1e-29. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.49 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **2.98%** (eas) · FAF95 2.85% · FAF99 2.8% · 1,336/44,774 in the highest group · 1,351/1,613,448 alleles overall — low-frequency (popmax 2.98%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 2.98% | 34 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,680 |
| South Asian | 0.00329% | 30,354 |
| Admixed American | 0.00167% | 59,960 |

*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}

Residue **90** lies in a UniProt-annotated variant site (in pg4d; type i; degradation in the cytoplasm due to defects in maturation); a β-strand.

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 2026-01-05.

**Submitter consensus:** conflicting (6 Pathogenic, 2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 9 submissions (2002–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2020-06-09 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-20 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-04-01 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2016-09-26 |
| Reproductive Health Research and Development, BGI Genomics | Pathogenic | no assertion criteria provided | curation | 2020-01-06 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-08 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2023-02-02 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-10 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inherited bleeding disorder, platelet-type, Platelet-type bleeding disorder 10, not specified, not provided, Platelet disorder, Platelet-type bleeding disorder, AllHighlyPenetrant, none provided, CD36 DEFICIENCY.

## Similar variants {#similar}

Related CD36 variant pages (same residue, condition, or type): [CD36 c.1254+1G>A](/variant/cd36-c-1254-plus-1g-a), [CD36 c.430-2A>G](/variant/cd36-c-430-minus-2a-g), [CD36 p.Cys243Ter](/variant/cd36-p-cys243ter), [CD36 p.Leu381Ter](/variant/cd36-p-leu381ter), [CD36 p.Tyr62Ter](/variant/cd36-p-tyr62ter), [CD36 c.-27C>T](/variant/cd36-c-minus-27c-t), [CD36 p.Ala427Ser](/variant/cd36-p-ala427ser), [CD36 p.Arg292Ile](/variant/cd36-p-arg292ile).

### 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 13535). 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.*