# NM_001127.4(AP1B1):c.2333C>G (p.Pro778Arg)

https://sugi.bio/variant/ap1b1-p-pro778arg

## Summary

**AP1B1 p.Pro778Arg (c.2333C>G)** is classified **Uncertain significance** in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: ambiguous (0.4141); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the AP1B1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [AP1B1](https://sugi.bio/atlas/gene/AP1B1/) |
| Protein change (HGVS p.) | p.Pro778Arg |
| Coding change (HGVS c.) | c.2333C>G |
| MANE Select transcript | [NM_001127](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127) |
| Variant type | single nucleotide variant |
| Location | chr22:29331893-29331893 (GRCh38) |
| ClinVar | [VCV3921995](https://www.ncbi.nlm.nih.gov/clinvar/variation/3921995/) |

**All HGVS expressions:** `NC_000022.10:g.29727882G>C`, `NC_000022.11:g.29331893G>C`, `NM_001127.4:c.2333C>G`, `NM_001166019.2:c.2252C>G`, `NM_001378562.1:c.2333C>G`, `NM_001378563.1:c.2312C>G`, `NM_001378564.1:c.2162C>G`, `NM_001378565.1:c.2141C>G`, `NM_001378566.1:c.2126C>G`, `NM_145730.3:c.2312C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4141) — no call either way
- REVEL 0.37 (indeterminate)
- SaProt LLR -13.723 (damaging)
- SpliceAI predicts **acceptor loss** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.845, GERP 1.55, phastCons 1 — highly conserved
- CADD: **PHRED 24.3**. 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 0.86** across the covering region of the MANE Select transcript (29,328,824–29,341,571), spanning 12,747 bp. Chi-square p 0.0016. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.39**, donor loss **0.00**, acceptor gain **0.11**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.39**, donor loss **0.00**, acceptor gain **0.11**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,178,878 in the highest group · 5/1,611,864 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00475% | 21,075 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,438 |

Finnish 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}

**AP1B1** population constraint: LOEUF 0.476, pLI 0.99357, missense-Z 3.2212. *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):

- **ichthyosiform erythroderma, corneal involvement, and hearing loss** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.46, 57% of residues very-high.

**20 experimental structure(s)** (PDB): [4HMY](https://www.rcsb.org/structure/4HMY), [4P6Z](https://www.rcsb.org/structure/4P6Z), [6CM9](https://www.rcsb.org/structure/6CM9), [6CRI](https://www.rcsb.org/structure/6CRI), [6D83](https://www.rcsb.org/structure/6D83), [6D84](https://www.rcsb.org/structure/6D84) — incl. mutant structure 6D83.

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

*Describes the biological roles of AP1B1 (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:** AP1B1 participates in disease-associated pathways. In Reactome, AP1B1 is annotated in disease pathway(s) including **Nef mediated downregulation of MHC class I complex cell surface expression**.

**Disease mechanism (Reactome):** AP1B1 loss or alteration is curated in [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940).

### Pathways affected {#pathways}

AP1B1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940) | curated |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-25.

**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 | 2025-05-25 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related AP1B1 variant pages (same residue, condition, or type): [AP1B1 p.Asp234Asn](/variant/ap1b1-p-asp234asn), [AP1B1 p.Gly568Ser](/variant/ap1b1-p-gly568ser), [AP1B1 c.2310-3C>G](/variant/ap1b1-c-2310-minus-3c-g), [AP1B1 p.Ala254Thr](/variant/ap1b1-p-ala254thr), [AP1B1 p.Ala352Thr](/variant/ap1b1-p-ala352thr), [AP1B1 p.Ala410Thr](/variant/ap1b1-p-ala410thr), [AP1B1 p.Ala598Val](/variant/ap1b1-p-ala598val), [AP1B1 p.Ala689Pro](/variant/ap1b1-p-ala689pro).

### 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 3921995). 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.*