# NM_005845.5(ABCC4):c.969A>G (p.Ser323=)

https://sugi.bio/variant/abcc4-p-ser323

## Summary

**ABCC4 p.Ser323= (c.969A>G)** is classified **Benign** in ABCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). Common (popmax 68.8%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · 1 submitter · common (popmax 68.8%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ABCC4 gene that is classified as benign — not considered disease-causing, 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 | [ABCC4](https://sugi.bio/atlas/gene/ABCC4/) |
| Protein change (HGVS p.) | p.Ser323= |
| Coding change (HGVS c.) | c.969A>G |
| MANE Select transcript | [NM_005845](https://www.ncbi.nlm.nih.gov/nuccore/NM_005845) |
| Variant type | single nucleotide variant |
| Location | chr13:95206724-95206724 (GRCh38) |
| ClinVar | [VCV4683820](https://www.ncbi.nlm.nih.gov/clinvar/variation/4683820/) |

**All HGVS expressions:** `LRG_1183:g.99723A>G`, `LRG_1183t1:c.969A>G`, `NC_000013.10:g.95858978T>C`, `NC_000013.11:g.95206724T>C`, `NG_050651.2:g.99723A>G`, `NM_001105515.3:c.969A>G`, `NM_001301829.2:c.969A>G`, `NM_001301830.2:c.744A>G`, `NM_005845.5:c.969A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 68.8%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP -13.086, GERP -3.15 — fast-evolving / accelerated position
- CADD: **PHRED 0.077**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.44 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 **68.8%** (afr) · FAF95 68.3% · FAF99 68.1% · 51,574/74,932 in the highest group · 1,054,134/1,613,838 alleles overall — common (popmax 68.8%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 68.8% | 1 |
| European (non-Finnish) | 66.4% | 2 |
| South Asian | 64.3% | 2 |
| Finnish (not grpmax-eligible) | 63.6% | 2 |
| Remaining individuals (not grpmax-eligible) | 63.4% | 2 |
| Amish (not grpmax-eligible) | 62.2% | 2 |
| Admixed American | 58% | 2 |
| Middle Eastern | 56.8% | 2 |
| East Asian | 55.5% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 54.4% | 2 |

*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}

**ABCC4** population constraint: LOEUF 0.647, pLI 7.0811e-11, missense-Z 2.2737. *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):

- **qualitative platelet defect** — Moderate (AR)

## Protein context {#protein}

Residue **323** lies in an α-helix; the abc transmembrane type-1 1 domain.

AlphaFold model confidence (whole protein): pLDDT 83.42, 46% of residues very-high.

**25 experimental structure(s)** (PDB): [8BJF](https://www.rcsb.org/structure/8BJF), [8BWO](https://www.rcsb.org/structure/8BWO), [8BWP](https://www.rcsb.org/structure/8BWP), [8BWQ](https://www.rcsb.org/structure/8BWQ), [8BWR](https://www.rcsb.org/structure/8BWR), [8I4A](https://www.rcsb.org/structure/8I4A).

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

*Describes the biological roles of ABCC4 (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:** ABCC4's established molecular role includes guanine nucleotide transmembrane transporter activity. p.Ser323= falls in the abc transmembrane type-1 1 domain.


### Pathways affected {#pathways}

ABCC4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [Azathioprine ADME](https://reactome.org/content/detail/R-HSA-9748787) | curated |
| [Paracetamol ADME](https://reactome.org/content/detail/R-HSA-9753281) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

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

**Molecular function:** guanine nucleotide transmembrane transporter activity, prostaglandin transmembrane transporter activity, urate transmembrane transporter activity, purine nucleotide transmembrane transporter activity, ABC-type glutathione S-conjugate transporter activity, ABC-type bile acid transporter activity.

**Biological process:** bile acid and bile salt transport, prostaglandin transport, urate transport, prostaglandin secretion, cilium assembly, cAMP transport.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-29.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-29 |

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

## Similar variants {#similar}

Related ABCC4 variant pages (same residue, condition, or type): [ABCC4 p.Ala1282Thr](/variant/abcc4-p-ala1282thr), [ABCC4 p.Ala1324Thr](/variant/abcc4-p-ala1324thr), [ABCC4 p.Leu238Phe](/variant/abcc4-p-leu238phe), [ABCC4 p.Tyr788Cys](/variant/abcc4-p-tyr788cys), [ABCC4 c.1825-7A>G](/variant/abcc4-c-1825-minus-7a-g), [ABCC4 c.185+7C>T](/variant/abcc4-c-185-plus-7c-t), [ABCC4 c.307-10C>T](/variant/abcc4-c-307-minus-10c-t), [ABCC4 p.Ala700=](/variant/abcc4-p-ala700).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 4683820). 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.*