# NM_000384.3(APOB):c.118C>T (p.Pro40Ser)

https://sugi.bio/variant/apob-p-pro40ser

## Summary

**APOB p.Pro40Ser (c.118C>T)** is classified **Likely benign** in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-07). AlphaMissense: likely benign (0.077); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the APOB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [APOB](https://sugi.bio/atlas/gene/APOB/) |
| Protein change (HGVS p.) | p.Pro40Ser |
| Coding change (HGVS c.) | c.118C>T |
| MANE Select transcript | [NM_000384](https://www.ncbi.nlm.nih.gov/nuccore/NM_000384) |
| Variant type | single nucleotide variant |
| Location | chr2:21043516-21043516 (GRCh38) |
| ClinVar | [VCV3307589](https://www.ncbi.nlm.nih.gov/clinvar/variation/3307589/) |

**All HGVS expressions:** `NC_000002.11:g.21266388G>A`, `NC_000002.12:g.21043516G>A`, `NG_011793.1:g.5558C>T`, `NG_011793.2:g.5557C>T`, `NG_042873.1:g.2529G>A`, `NM_000384.3:c.118C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.077)
- REVEL 0.039 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -1.527, GERP -2.09 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 0.408**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.22 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: **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 3/3, triplosensitivity 0/3. *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 **40** lies in the 'heparin-binding' region.

**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.Pro40Ser falls in the heparin-binding region.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-07 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related APOB variant pages (same residue, condition, or type): [APOB p.Arg490Trp](/variant/apob-p-arg490trp), [APOB c.1124+3A>G](/variant/apob-c-1124-plus-3a-g), [APOB c.11788+4A>G](/variant/apob-c-11788-plus-4a-g), [APOB c.12087+2T>C](/variant/apob-c-12087-plus-2t-c), [APOB p.Ala1320Thr](/variant/apob-p-ala1320thr), [APOB p.Ala1695Val](/variant/apob-p-ala1695val), [APOB p.Ala1975Ser](/variant/apob-p-ala1975ser), [APOB p.Ala3008Thr](/variant/apob-p-ala3008thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3307589). 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.*