# NM_022437.3(ABCG8):c.14C>T (p.Ala5Val)

https://sugi.bio/variant/abcg8-p-ala5val

## Summary

**ABCG8 p.Ala5Val (c.14C>T)** is classified **Likely benign** in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-29). AlphaMissense: likely benign (0.0786); Very rare (popmax 0.00196%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00196%, amr)

## For patients & families {#patients}

This is a change in the ABCG8 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [ABCG8](https://sugi.bio/atlas/gene/ABCG8/) |
| Protein change (HGVS p.) | p.Ala5Val |
| Coding change (HGVS c.) | c.14C>T |
| MANE Select transcript | [NM_022436](https://www.ncbi.nlm.nih.gov/nuccore/NM_022436) (variant reported on NM_022437) |
| Variant type | single nucleotide variant |
| Location | chr2:43839067-43839067 (GRCh38) |
| ClinVar | [VCV3419095](https://www.ncbi.nlm.nih.gov/clinvar/variation/3419095/) |

**All HGVS expressions:** `LRG_1181:g.4753G>A`, `LRG_1182:g.12126C>T`, `LRG_1182t1:c.14C>T`, `NC_000002.11:g.44066206C>T`, `NC_000002.12:g.43839067C>T`, `NG_008883.1:g.4753G>A`, `NG_008884.2:g.12126C>T`, `NM_001357321.2:c.14C>T`, `NM_022437.3:c.14C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0786)
- REVEL 0.142 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.59 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.284, GERP -2.3 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.253**. 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 1.29** across the covering region of the MANE Select transcript (43,839,054–43,877,910), spanning 38,856 bp. Chi-square p 8.8e-18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00196%** (amr) · FAF95 0.000254% · FAF99 0.000163% · 1/50,990 in the highest group · 9/1,398,724 alleles overall — very rare (popmax 0.00196%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00196% | 50,990 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,076 |
| European (non-Finnish) | 0.00061% | 163,825 |

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-29 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

### 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 3419095). 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.*