# NM_133173.3(APBB3):c.833T>C (p.Val278Ala)

https://sugi.bio/variant/apbb3-p-val278ala

## Summary

**APBB3 p.Val278Ala (c.833T>C)** is classified **Uncertain significance** in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). AlphaMissense: likely benign (0.133); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs779261685 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the APBB3 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 | [APBB3](https://sugi.bio/atlas/gene/APBB3/) |
| Protein change (HGVS p.) | p.Val278Ala |
| Coding change (HGVS c.) | c.833T>C |
| MANE Select transcript | [NM_133173](https://www.ncbi.nlm.nih.gov/nuccore/NM_133173) |
| dbSNP | [rs779261685](https://www.ncbi.nlm.nih.gov/snp/rs779261685/) |
| Variant type | single nucleotide variant |
| Location | chr5:140561101-140561101 (GRCh38) |
| ClinVar | [VCV2471211](https://www.ncbi.nlm.nih.gov/clinvar/variation/2471211/) |

**All HGVS expressions:** `NC_000005.10:g.140561101A>G`, `NC_000005.9:g.139940686A>G`, `NG_031847.1:g.1993T>C`, `NM_006051.4:c.854T>C`, `NM_133172.3:c.848T>C`, `NM_133173.3:c.833T>C`, `NM_133174.3:c.827T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.133)
- REVEL 0.051 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.075 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.44, GERP -1.67, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 18.36**. 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 0.84** across the covering region of the MANE Select transcript (140,560,426–140,564,245), spanning 3,819 bp. Chi-square p 0.00036. 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 (A>T, Δ0.29 acceptor 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,928 in the highest group · 4/1,613,988 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| African / African-American (grpmax) | 0.00267% | 37,464 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**APBB3** population constraint: LOEUF 0.973, pLI 1.3447e-13, missense-Z 1.6916. *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 **278** lies in the pid 1 domain.

AlphaFold model confidence (whole protein): pLDDT 64.76, 21% of residues very-high.

**2 experimental structure(s)** (PDB): [2DYQ](https://www.rcsb.org/structure/2DYQ), [2YSC](https://www.rcsb.org/structure/2YSC).

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

*Describes the biological roles of APBB3 (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:** APBB3's established molecular role includes low-density lipoprotein particle receptor binding. p.Val278Ala falls in the pid 1 domain.


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

**Molecular function:** low-density lipoprotein particle receptor binding.

**Biological process:** positive regulation of protein secretion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-06.

**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 | 2023-02-06 |

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

## Similar variants {#similar}

Related APBB3 variant pages (same residue, condition, or type): [APBB3 p.Ala135Gly](/variant/apbb3-p-ala135gly), [APBB3 p.Ala151Val](/variant/apbb3-p-ala151val), [APBB3 p.Ala163Thr](/variant/apbb3-p-ala163thr), [APBB3 p.Ala288Thr](/variant/apbb3-p-ala288thr), [APBB3 p.Ala313Val](/variant/apbb3-p-ala313val), [APBB3 p.Ala475Asp](/variant/apbb3-p-ala475asp), [APBB3 p.Arg122Cys](/variant/apbb3-p-arg122cys), [APBB3 p.Arg154Cys](/variant/apbb3-p-arg154cys).

### 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 2471211). 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.*