# NM_000384.3(APOB):c.1644C>G (p.Phe548Leu)

https://sugi.bio/variant/apob-p-phe548leu

## Summary

**APOB p.Phe548Leu (c.1644C>G)** is classified **Uncertain significance** in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely pathogenic (0.7519); Absent from gnomAD v4.1; Associated with familial hypobetalipoproteinemia 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the APOB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to familial hypobetalipoproteinemia 1.

*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 | 7 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002876/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [APOB](https://sugi.bio/atlas/gene/APOB/) |
| Protein change (HGVS p.) | p.Phe548Leu |
| Coding change (HGVS c.) | c.1644C>G |
| MANE Select transcript | [NM_000384](https://www.ncbi.nlm.nih.gov/nuccore/NM_000384) |
| Variant type | single nucleotide variant |
| Location | chr2:21028512-21028512 (GRCh38) |
| ClinVar | [VCV3748021](https://www.ncbi.nlm.nih.gov/clinvar/variation/3748021/) |

**All HGVS expressions:** `NC_000002.11:g.21251384G>C`, `NC_000002.12:g.21028512G>C`, `NG_011793.1:g.20562C>G`, `NG_011793.2:g.20561C>G`, `NM_000384.3:c.1644C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7519)
- REVEL 0.143 (moderately benign-leaning) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL does not
- Conservation: phyloP 3.879, GERP -0.411, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in APOB (of 27,000 modeled).
- CADD: **PHRED 14.92**. 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 1.00** across the covering region of the MANE Select transcript (21,011,636–21,043,945), spanning 32,309 bp. Chi-square p 0.91. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**APOB** population constraint: LOEUF 0.537, pLI 1.3512e-11, missense-Z 0.96416; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypercholesterolemia, autosomal dominant, type B** — Definitive (AD)
- **familial hypobetalipoproteinemia 1** — Definitive (SD)

## Protein context {#protein}

Residue **548** lies in the vitellogenin domain.

**8 experimental structure(s)** (PDB): [9BD1](https://www.rcsb.org/structure/9BD1), [9BD8](https://www.rcsb.org/structure/9BD8), [9BDE](https://www.rcsb.org/structure/9BDE), [9BDT](https://www.rcsb.org/structure/9BDT), [9COO](https://www.rcsb.org/structure/9COO), [9E9R](https://www.rcsb.org/structure/9E9R).

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

*Describes the biological roles of APOB (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:** APOB's established molecular role includes phospholipid binding. p.Phe548Leu falls in the vitellogenin domain.


### Pathways affected {#pathways}

APOB participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Chylomicron assembly](https://reactome.org/content/detail/R-HSA-8963888) | curated |
| [Chylomicron remodeling](https://reactome.org/content/detail/R-HSA-8963901) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | curated |
| [LDL remodeling](https://reactome.org/content/detail/R-HSA-8964041) | curated |
| [Platelet sensitization by LDL](https://reactome.org/content/detail/R-HSA-432142) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of TLR by endogenous ligand](https://reactome.org/content/detail/R-HSA-5686938) | curated |
| [Scavenging by Class H Receptors](https://reactome.org/content/detail/R-HSA-3000497) | curated |
| [VLDL assembly](https://reactome.org/content/detail/R-HSA-8866423) | curated |
| [Chylomicron clearance](https://reactome.org/content/detail/R-HSA-8964026) | electronic |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | electronic |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | electronic |
| [Scavenging by Class A Receptors](https://reactome.org/content/detail/R-HSA-3000480) | electronic |
| [Scavenging by Class B Receptors](https://reactome.org/content/detail/R-HSA-3000471) | electronic |
| [Scavenging by Class F Receptors](https://reactome.org/content/detail/R-HSA-3000484) | electronic |
| [VLDL clearance](https://reactome.org/content/detail/R-HSA-8964046) | electronic |

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

**Molecular function:** phospholipid binding, heparin binding, lipase binding, receptor ligand activity, low-density lipoprotein particle receptor binding, cholesterol transfer activity.

**Biological process:** cholesterol metabolic process, response to virus, positive regulation of macrophage derived foam cell differentiation, positive regulation of lipid storage, positive regulation of cholesterol storage, cholesterol transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-11 |

## Associated conditions {#conditions}

[familial hypobetalipoproteinemia 1](https://sugi.bio/atlas/disease/familial-hypobetalipoproteinemia-1/), [hypercholesterolemia, autosomal dominant, type B](https://sugi.bio/atlas/disease/hypercholesterolemia-autosomal-dominant-type-b/).

**Reported phenotype names (ClinVar):** Familial hypobetalipoproteinemia 1, Hypercholesterolemia, autosomal dominant, type B, APOB-Related Familial Hypobetalipoproteinemia, Hypobetalipoproteinemia, normotriglyceridemic, Acanthocytosis with hypobetalipoproteinemia, Familial Hypercholesterolemia Type B, APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE, APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE, HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B, Hyperlipoproteinemia Type IIb.

## Similar variants {#similar}

Related APOB variant pages (same residue, condition, or type): [APOB p.Phe548=](/variant/apob-p-phe548), [APOB c.1830-1G>A](/variant/apob-c-1830-minus-1g-a), [APOB c.2604+1G>A](/variant/apob-c-2604-plus-1g-a), [APOB c.537+1G>T](/variant/apob-c-537-plus-1g-t), [APOB p.Arg1333Ter](/variant/apob-p-arg1333ter), [APOB p.Arg2012Ter](/variant/apob-p-arg2012ter), [APOB p.Arg2085Ter](/variant/apob-p-arg2085ter), [APOB p.Arg2513Ter](/variant/apob-p-arg2513ter).

### 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 3748021). 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.*