# NM_003917.5(AP1G2):c.1643T>C (p.Val548Ala)

https://sugi.bio/variant/ap1g2-p-val548ala

## Summary

**AP1G2 p.Val548Ala (c.1643T>C)** is classified **Uncertain significance** in AP1G2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely benign (0.1617); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AP1G2 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 | [AP1G2](https://sugi.bio/atlas/gene/AP1G2/) |
| Protein change (HGVS p.) | p.Val548Ala |
| Coding change (HGVS c.) | c.1643T>C |
| MANE Select transcript | [NM_003917](https://www.ncbi.nlm.nih.gov/nuccore/NM_003917) |
| Variant type | single nucleotide variant |
| Location | chr14:23562052-23562052 (GRCh38) |
| ClinVar | [VCV3876580](https://www.ncbi.nlm.nih.gov/clinvar/variation/3876580/) |

**All HGVS expressions:** `NC_000014.8:g.24031261A>G`, `NC_000014.9:g.23562052A>G`, `NG_011937.1:g.11019T>C`, `NG_128788.1:g.76A>G`, `NM_001282474.2:c.500T>C`, `NM_001282475.2:c.1427T>C`, `NM_001354673.2:c.1256T>C`, `NM_001354674.2:c.500T>C`, `NM_001354675.2:c.500T>C`, `NM_001354677.2:c.500T>C`, `NM_001354681.2:c.500T>C`, `NM_003917.5:c.1643T>C`, `NR_148937.2:n.2432T>C`, `NR_148938.2:n.1958T>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** (0.1617)
- REVEL 0.339 (indeterminate)
- SaProt LLR -7.633 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.938, GERP 2.33, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.3**. 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 0.96** across the covering region of the MANE Select transcript (23,559,752–23,567,314), spanning 7,562 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**. Largest is acceptor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.20** (loss), gain 0.05 / loss 0.20. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**AP1G2** population constraint: LOEUF 1.004, pLI 1.5854e-23, missense-Z 1.009. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.13, 56% of residues very-high.

**4 experimental structure(s)** (PDB): [2E9G](https://www.rcsb.org/structure/2E9G), [2YMT](https://www.rcsb.org/structure/2YMT), [3ZHF](https://www.rcsb.org/structure/3ZHF), [4BCX](https://www.rcsb.org/structure/4BCX).

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

*Describes the biological roles of AP1G2 (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.*


### Pathways affected {#pathways}

AP1G2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-16.

**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 | 2025-01-16 |

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

## Similar variants {#similar}

Related AP1G2 variant pages (same residue, condition, or type): [AP1G2 p.Val548Met](/variant/ap1g2-p-val548met), [AP1G2 p.Ala181Pro](/variant/ap1g2-p-ala181pro), [AP1G2 p.Ala360Thr](/variant/ap1g2-p-ala360thr), [AP1G2 p.Ala430Val](/variant/ap1g2-p-ala430val), [AP1G2 p.Ala465Glu](/variant/ap1g2-p-ala465glu), [AP1G2 p.Ala508Thr](/variant/ap1g2-p-ala508thr), [AP1G2 p.Ala527Val](/variant/ap1g2-p-ala527val), [AP1G2 p.Ala76Thr](/variant/ap1g2-p-ala76thr).

### 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 3876580). 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.*