# NM_001353788.2(APBA2):c.1224A>G (p.Gln408=)

https://sugi.bio/variant/apba2-p-gln408

## Summary

**APBA2 p.Gln408= (c.1224A>G)** is classified **Likely benign** in APBA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Rare (popmax 0.368%, afr); Associated with APBA2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs140018484 · 1 submitter · 1 linked condition · rare (popmax 0.368%, afr)

## For patients & families {#patients}

This is a change in the APBA2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to APBA2-related disorder.

*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 | [APBA2](https://sugi.bio/atlas/gene/APBA2/) |
| Protein change (HGVS p.) | p.Gln408= |
| Coding change (HGVS c.) | c.1224A>G |
| MANE Select transcript | [NM_001353788](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353788) |
| dbSNP | [rs140018484](https://www.ncbi.nlm.nih.gov/snp/rs140018484/) |
| Variant type | single nucleotide variant |
| Location | chr15:29094286-29094286 (GRCh38) |
| ClinVar | [VCV3052721](https://www.ncbi.nlm.nih.gov/clinvar/variation/3052721/) |

**All HGVS expressions:** `NC_000015.10:g.29094286A>G`, `NC_000015.9:g.29386489A>G`, `NM_001130414.1:c.1215+1066A>G`, `NM_001353788.2:c.1224A>G`, `NM_001353789.2:c.1224A>G`, `NM_001353790.2:c.1224A>G`, `NM_001353791.2:c.1224A>G`, `NM_001353792.2:c.1215+1066A>G`, `NM_001353793.2:c.1215+1066A>G`, `NM_001353794.2:c.1215+1066A>G`, `NM_001353795.2:c.1224A>G`, `NM_001353796.2:c.336A>G`, `NM_001353797.2:c.327+1066A>G`, `NM_001379685.1:c.1224A>G`, `NM_005503.3:c.1224A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.746, GERP -3.09 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.367**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.19**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.19**.
- Population frequency (gnomAD v4.1): grpmax **0.368%** (afr) · FAF95 0.332% · FAF99 0.318% · 276/75,054 in the highest group · 299/1,614,198 alleles overall — rare (popmax 0.368%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.368% | 272 |
| Remaining individuals (not grpmax-eligible) | 0.0272% | 3,677 |
| Admixed American | 0.00833% | 12,005 |
| European (non-Finnish) | 8.47e-05% | 1,180,034 |

*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}

**APBA2** population constraint: LOEUF 0.524, pLI 0.78163, missense-Z 2.9096. *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 **408** lies in the pid domain.

AlphaFold model confidence (whole protein): pLDDT 59.74, 17% of residues very-high.

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

*Describes the biological roles of APBA2 (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:** APBA2's established molecular role includes identical protein binding. p.Gln408= falls in the pid domain.


### Pathways affected {#pathways}

APBA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |

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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-10-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-28 |

## Associated conditions {#conditions}

[APBA2-related disorder](https://sugi.bio/atlas/disease/apba2-related-disorder/).

**Reported phenotype names (ClinVar):** APBA2-related disorder, APBA2-related condition.

## Similar variants {#similar}

Related APBA2 variant pages (same residue, condition, or type): [APBA2 c.1070-9C>T](/variant/apba2-c-1070-minus-9c-t), [APBA2 c.952-3825C>T](/variant/apba2-c-952-minus-3825c-t), [APBA2 c.*7C>T](/variant/apba2-c-star-7c-t), [APBA2 p.Arg52Gln](/variant/apba2-p-arg52gln), [APBA2 p.Asn704=](/variant/apba2-p-asn704), [APBA2 p.Asn722Ser](/variant/apba2-p-asn722ser), [APBA2 p.Asp162=](/variant/apba2-p-asp162), [APBA2 p.Gly603=](/variant/apba2-p-gly603).

### 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 3052721). 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.*