# NM_001001548.3(CD36):c.1030C>T (p.Pro344Ser)

https://sugi.bio/variant/cd36-p-pro344ser

## Summary

**CD36 p.Pro344Ser (c.1030C>T)** is classified **Uncertain significance** in CD36 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely pathogenic (0.9786); Very rare (popmax 0.00263%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs879729491 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00263%, nfe)

## 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.

*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.Pro344Ser |
| Coding change (HGVS c.) | c.1030C>T |
| MANE Select transcript | [NM_001001548](https://www.ncbi.nlm.nih.gov/nuccore/NM_001001548) |
| dbSNP | [rs879729491](https://www.ncbi.nlm.nih.gov/snp/rs879729491/) |
| Variant type | single nucleotide variant |
| Location | chr7:80671945-80671945 (GRCh38) |
| ClinVar | [VCV2405387](https://www.ncbi.nlm.nih.gov/clinvar/variation/2405387/) |

**All HGVS expressions:** `NC_000007.13:g.80301261C>T`, `NC_000007.14:g.80671945C>T`, `NG_008192.1:g.74758C>T`, `NM_000072.3:c.1030C>T`, `NM_001001547.3:c.1030C>T`, `NM_001001548.3:c.1030C>T`, `NM_001127443.2:c.1030C>T`, `NM_001127444.2:c.1030C>T`, `NM_001289908.1:c.913C>T`, `NM_001289909.1:c.850C>T`, `NM_001289911.2:c.802C>T`, `NM_001371074.1:c.1030C>T`, `NM_001371075.1:c.1030C>T`, `NM_001371077.1:c.1030C>T`, `NM_001371078.1:c.1030C>T`, `NM_001371079.1:c.928C>T`, `NM_001371080.1:c.565C>T`, `NM_001371081.1:c.565C>T`, `NR_110501.1:n.1021C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9786)
- REVEL 0.918 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.095 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.524, GERP 2.03, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CD36 (of 2,789 modeled).
- CADD: **PHRED 33.0**. 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.*
- 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 deltas (raw): acceptor loss **0.09**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Pangolin: Δ**0.40** (gain), gain 0.40 / loss 0.18. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00263%** (nfe) · FAF95 0.00189% · FAF99 0.00164% · 31/1,178,182 in the highest group · 34/1,611,262 alleles overall — very rare (popmax 0.00263%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00263% | 38,006 |
| East Asian | 0.00224% | 44,678 |
| Admixed American | 0.00167% | 59,912 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,356 |

*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 **344** lies in an α-helix.

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 2021-09-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-16 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD36 variant pages (same residue, condition, or type): [CD36 p.Pro344Leu](/variant/cd36-p-pro344leu), [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).

### 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 2405387). 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.*