# NM_000384.3(APOB):c.1785C>G (p.Ser595=)

https://sugi.bio/variant/apob-p-ser595

## Summary

**APOB p.Ser595= (c.1785C>G)** is classified **Benign/Likely benign** in APOB (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.78%, amr); Associated with hypercholesterolemia, autosomal dominant, type B.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs139864087 · 12 submitters · 4 linked conditions · low-frequency (popmax 3.78%, amr)

## For patients & families {#patients}

This is a change in the APOB gene that is classified as benign/likely benign — not considered disease-causing, submitted by 12 submitters, and is linked to hypercholesterolemia, autosomal dominant, type B.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027779/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.Ser595= |
| Coding change (HGVS c.) | c.1785C>G |
| MANE Select transcript | [NM_000384](https://www.ncbi.nlm.nih.gov/nuccore/NM_000384) |
| dbSNP | [rs139864087](https://www.ncbi.nlm.nih.gov/snp/rs139864087/) |
| Variant type | single nucleotide variant |
| Location | chr2:21028371-21028371 (GRCh38) |
| ClinVar | [VCV334171](https://www.ncbi.nlm.nih.gov/clinvar/variation/334171/) |

**All HGVS expressions:** `NC_000002.11:g.21251243G>C`, `NC_000002.12:g.21028371G>C`, `NG_011793.1:g.20703C>G`, `NM_000384.3:c.1785C>G`

## 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 1.402, GERP 0.724, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.551**. 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** — 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 (gnomAD v4.1): grpmax **3.78%** (amr) · FAF95 3.65% · FAF99 3.59% · 2,266/60,020 in the highest group · 2,387/1,614,142 alleles overall — low-frequency (popmax 3.78%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 3.78% | 26 |
| Remaining individuals (not grpmax-eligible) | 0.0976% | 1,025 |
| African / African-American | 0.056% | 1,786 |
| European (non-Finnish) | 0.00153% | 65,557 |

*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 **595** 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.Ser595= 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (9 Benign, 4 Likely benign).

**Submission history:** 13 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Robarts Research Institute, Western University | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-02 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-21 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2023-06-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-09-21 |
| GENinCode PLC | Benign | criteria provided, single submitter | clinical testing | 2024-06-19 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-08 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-10-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-05-30 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hypercholesterolemia, autosomal dominant, type B, Familial hypobetalipoproteinemia 1, Hypercholesterolemia, familial, 1, not provided, Cardiovascular phenotype, APOB-related disorder, Familial hypercholesterolemia, not specified, APOB-related condition, APOB-related disorders.

## Similar variants {#similar}

Related APOB variant pages (same residue, condition, or type): [APOB p.Ser595Phe](/variant/apob-p-ser595phe), [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 334171). 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.*