# NM_004886.4(APBA3):c.668C>T (p.Ala223Val)

https://sugi.bio/variant/apba3-p-ala223val

## Summary

**APBA3 p.Ala223Val (c.668C>T)** is classified **Uncertain significance** in APBA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely benign (0.3066); Ultra-rare (popmax 0.0487%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs748772419 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0487%, sas)

## For patients & families {#patients}

This is a change in the APBA3 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 | [APBA3](https://sugi.bio/atlas/gene/APBA3/) |
| Protein change (HGVS p.) | p.Ala223Val |
| Coding change (HGVS c.) | c.668C>T |
| MANE Select transcript | [NM_004886](https://www.ncbi.nlm.nih.gov/nuccore/NM_004886) |
| dbSNP | [rs748772419](https://www.ncbi.nlm.nih.gov/snp/rs748772419/) |
| Variant type | single nucleotide variant |
| Location | chr19:3754289-3754289 (GRCh38) |
| ClinVar | [VCV2590482](https://www.ncbi.nlm.nih.gov/clinvar/variation/2590482/) |

**All HGVS expressions:** `NC_000019.10:g.3754289G>A`, `NC_000019.9:g.3754287G>A`, `NM_004886.4:c.668C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3066)
- REVEL 0.491 (indeterminate)
- SaProt LLR -12.413 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 8.464, GERP 1.92, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.8**. 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 1.05** across the covering region of the MANE Select transcript (3,751,029–3,760,264), spanning 9,235 bp. Chi-square p 0.12. 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 (G>T, Δ0.28 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 **0.0487%** (sas) · FAF95 0.0369% · FAF99 0.0327% · 41/84,124 in the highest group · 47/1,401,060 alleles overall — ultra-rare (popmax 0.0487%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0487% | 2,052 |
| Admixed American | 0.00601% | 16,635 |
| Remaining individuals (not grpmax-eligible) | 0.00499% | 20,059 |

*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}

**APBA3** population constraint: LOEUF 1.237, pLI 2.3681e-15, missense-Z -1.6329. *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 **223** lies in the pid domain; the 'required for interaction with necab3' region.

AlphaFold model confidence (whole protein): pLDDT 64.79, 14% of residues very-high.

**3 experimental structure(s)** (PDB): [2YT7](https://www.rcsb.org/structure/2YT7), [2YT8](https://www.rcsb.org/structure/2YT8), [5UWS](https://www.rcsb.org/structure/5UWS).

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

*Describes the biological roles of APBA3 (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:** APBA3's established molecular role includes enzyme inhibitor activity. p.Ala223Val falls in the pid domain.


### Pathways affected {#pathways}

APBA3 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:** enzyme inhibitor activity, enzyme binding.

**Biological process:** negative regulation of catalytic activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-30.

**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 | 2023-07-30 |

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

## Similar variants {#similar}

Related APBA3 variant pages (same residue, condition, or type): [APBA3 p.Ala158Val](/variant/apba3-p-ala158val), [APBA3 p.Ala202Val](/variant/apba3-p-ala202val), [APBA3 p.Ala308Val](/variant/apba3-p-ala308val), [APBA3 p.Ala317Val](/variant/apba3-p-ala317val), [APBA3 p.Ala335Thr](/variant/apba3-p-ala335thr), [APBA3 p.Ala335Val](/variant/apba3-p-ala335val), [APBA3 p.Ala351Thr](/variant/apba3-p-ala351thr), [APBA3 p.Ala352Thr](/variant/apba3-p-ala352thr).

### 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 2590482). 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.*