# NM_001288985.2(ABCA8):c.3710T>C (p.Ile1237Thr)

https://sugi.bio/variant/abca8-p-ile1237thr

## Summary

**ABCA8 p.Ile1237Thr (c.3710T>C)** is classified **Uncertain significance** in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). AlphaMissense: likely pathogenic (0.5879); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2509422781 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCA8 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 | [ABCA8](https://sugi.bio/atlas/gene/ABCA8/) |
| Protein change (HGVS p.) | p.Ile1237Thr |
| Coding change (HGVS c.) | c.3710T>C |
| MANE Select transcript | [NM_001288985](https://www.ncbi.nlm.nih.gov/nuccore/NM_001288985) |
| dbSNP | [rs2509422781](https://www.ncbi.nlm.nih.gov/snp/rs2509422781/) |
| Variant type | single nucleotide variant |
| Location | chr17:68882717-68882717 (GRCh38) |
| ClinVar | [VCV3114410](https://www.ncbi.nlm.nih.gov/clinvar/variation/3114410/) |

**All HGVS expressions:** `NC_000017.10:g.66878858A>G`, `NC_000017.11:g.68882717A>G`, `NM_001288985.2:c.3710T>C`, `NM_001288986.2:c.3708-13T>C`, `NM_001375771.1:c.3527T>C`, `NM_001375772.1:c.2288T>C`, `NM_007168.4:c.3590T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5879)
- REVEL 0.681 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -4.875 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 9.201, GERP 2.03, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.5**. 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 1.01** across the covering region of the MANE Select transcript (68,868,088–68,942,034), spanning 73,946 bp. Chi-square p 0.82. 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 (A>C, Δ0.80 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: **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}

**ABCA8** population constraint: LOEUF 1.086, pLI 9.1537e-44, missense-Z 0.53784. *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 **1237** lies in a UniProt-annotated variant site (loss of expression; loss of cholesterol efflux to apoa1).

AlphaFold model confidence (whole protein): pLDDT 78.67, 17% of residues very-high.

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

*Describes the biological roles of ABCA8 (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:** ABCA8's established molecular role includes ABC-type xenobiotic transporter activity.


### Pathways affected {#pathways}

ABCA8 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |

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

**Molecular function:** ABC-type xenobiotic transporter activity, ABC-type transporter activity.

**Biological process:** sphingomyelin biosynthetic process, xenobiotic transmembrane transport, regulation of cholesterol efflux, positive regulation of cholesterol efflux, cholesterol transport, cholesterol efflux.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-17.

**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 | 2023-11-17 |

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

## Similar variants {#similar}

Related ABCA8 variant pages (same residue, condition, or type): [ABCA8 p.Gly176Ser](/variant/abca8-p-gly176ser), [ABCA8 c.4200-1G>C](/variant/abca8-c-4200-minus-1g-c), [ABCA8 p.Gly1225Glu](/variant/abca8-p-gly1225glu), [ABCA8 p.Ile542=](/variant/abca8-p-ile542), [ABCA8 p.Met251Ile](/variant/abca8-p-met251ile), [ABCA8 c.3316-8G>T](/variant/abca8-c-3316-minus-8g-t), [ABCA8 p.Ala1109Val](/variant/abca8-p-ala1109val), [ABCA8 p.Ala1344Ser](/variant/abca8-p-ala1344ser).

### 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 3114410). 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.*