# NM_005502.4(ABCA1):c.254C>T (p.Pro85Leu)

https://sugi.bio/variant/abca1-p-pro85leu

## Summary

**ABCA1 p.Pro85Leu (c.254C>T)** is classified **Conflicting classifications of pathogenicity** in ABCA1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1745); Rare (popmax 0.158%, sas); Associated with Tangier disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs145183203 · 10 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.158%, sas)

## For patients & families {#patients}

This is a change in the ABCA1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, and is linked to Tangier disease.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA1 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Tangier disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertriglyceridemia — Very frequent (99-80%)
- Hypocholesterolemia — Very frequent (99-80%)
- Ectropion — Frequent (79-30%)
- Dry skin — Frequent (79-30%)
- Hepatosplenomegaly — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Distal muscle weakness — Frequent (79-30%)
- Chronic noninfectious lymphadenopathy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007731/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCA1](https://sugi.bio/atlas/gene/ABCA1/) |
| Protein change (HGVS p.) | p.Pro85Leu |
| Coding change (HGVS c.) | c.254C>T |
| MANE Select transcript | [NM_005502](https://www.ncbi.nlm.nih.gov/nuccore/NM_005502) |
| dbSNP | [rs145183203](https://www.ncbi.nlm.nih.gov/snp/rs145183203/) |
| Variant type | single nucleotide variant |
| Location | chr9:104884475-104884475 (GRCh38) |
| ClinVar | [VCV364464](https://www.ncbi.nlm.nih.gov/clinvar/variation/364464/) |

**All HGVS expressions:** `LRG_542:g.48681C>T`, `LRG_542t1:c.254C>T`, `NC_000009.11:g.107646756G>A`, `NC_000009.12:g.104884475G>A`, `NG_007981.1:g.48681C>T`, `NM_005502.4:c.254C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1745)
- REVEL 0.838 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -5.688 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 11.77, GERP 2.62, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.5**. 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 0.95** across the covering region of the MANE Select transcript (104,822,643–104,903,679), spanning 81,036 bp. Chi-square p 0.081. 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, Δ0.31 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 **0.158%** (sas) · FAF95 0.137% · FAF99 0.129% · 144/91,084 in the highest group · 2,156/1,614,202 alleles overall — rare (popmax 0.158%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.493% | 203 |
| South Asian (grpmax) | 0.158% | 633 |
| European (non-Finnish) | 0.133% | 749 |
| Remaining individuals (not grpmax-eligible) | 0.112% | 893 |
| Admixed American | 0.0533% | 1,876 |
| African / African-American | 0.0213% | 4,691 |
| Middle Eastern | 0.0165% | 6,062 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,802 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ABCA1** population constraint: LOEUF 0.563, pLI 2.3118e-12, missense-Z 3.076. *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 **85** lies in a disulfide bond; a UniProt-annotated variant site (in fha1; alabama).

AlphaFold model confidence (whole protein): pLDDT 73.50, 6% of residues very-high.

**7 experimental structure(s)** (PDB): [5XJY](https://www.rcsb.org/structure/5XJY), [7ROQ](https://www.rcsb.org/structure/7ROQ), [7TBW](https://www.rcsb.org/structure/7TBW), [7TBY](https://www.rcsb.org/structure/7TBY), [7TBZ](https://www.rcsb.org/structure/7TBZ), [7TC0](https://www.rcsb.org/structure/7TC0).

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

*Describes the biological roles of ABCA1 (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:** ABCA1's established molecular role includes signaling receptor binding. In Reactome, ABCA1 is annotated in disease pathway(s) including **Defective ABCA1 causes TGD**.

**Disease mechanism (Reactome):** ABCA1 loss or alteration is curated in [Defective ABCA1 causes TGD](https://reactome.org/content/detail/R-HSA-5682113).

### Pathways affected {#pathways}

ABCA1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCA1 causes TGD](https://reactome.org/content/detail/R-HSA-5682113) | curated |
| [HDL assembly](https://reactome.org/content/detail/R-HSA-8963896) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

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

**Molecular function:** signaling receptor binding, ATP binding, obsolete phospholipid transporter activity, syntaxin binding, phosphatidylcholine binding, small GTPase binding.

**Biological process:** lysosome organization, G protein-coupled receptor signaling pathway, adenylate cyclase-activating G protein-coupled receptor signaling pathway, cholesterol metabolic process, protein secretion, endosomal transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-05.

**Submitter consensus:** conflicting (7 Likely benign, 4 Uncertain significance).

**Submission history:** 11 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-01 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-12 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-24 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |
| Clinical Genetics, Academic Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-04-30 |

## Associated conditions {#conditions}

[Tangier disease](https://sugi.bio/atlas/disease/tangier-disease/), [hypoalphalipoproteinemia, primary, 1](https://sugi.bio/atlas/disease/hypoalphalipoproteinemia-primary-1/).

**Reported phenotype names (ClinVar):** Tangier disease, Hypoalphalipoproteinemia, primary, 1, not provided, not specified, ABCA1-related disorder, Cardiovascular phenotype, none provided, HIGH DENSITY LIPOPROTEIN DEFICIENCY, TANGIER TYPE, HIGH DENSITY LIPOPROTEIN DEFICIENCY, TYPE 1, Cholesterol thesaurismosis.

## Similar variants {#similar}

Related ABCA1 variant pages (same residue, condition, or type): [ABCA1 p.Pro85Ser](/variant/abca1-p-pro85ser), [ABCA1 p.Pro85=](/variant/abca1-p-pro85), [ABCA1 c.5237+3A>C](/variant/abca1-c-5237-plus-3a-c), [ABCA1 p.Arg2080Trp](/variant/abca1-p-arg2080trp), [ABCA1 p.Arg587Trp](/variant/abca1-p-arg587trp), [ABCA1 p.Asn1800His](/variant/abca1-p-asn1800his), [ABCA1 c.*2330A>T](/variant/abca1-c-star-2330a-t), [ABCA1 c.*379C>T](/variant/abca1-c-star-379c-t).

### 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 364464). 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.*