Is ABCA1 p.Pro85Leu (c.254C>T) pathogenic?

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.

What condition is associated with ABCA1 p.Pro85Leu (c.254C>T)?

ABCA1 p.Pro85Leu (c.254C>T) is associated with Tangier disease, hypoalphalipoproteinemia, primary, 1 (ClinVar).

How common is ABCA1 p.Pro85Leu (c.254C>T) in the general population?

ABCA1 p.Pro85Leu (c.254C>T) is rare (popmax 0.158%, sas) (gnomAD).

How is Tangier disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA1 p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely benign (score 0.1745) — an in-silico prediction, not a clinical call.

ABCA1 p.Pro85Leu

c.254C>T · rs145183203 · VCV364464

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1745 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tangier disease

Computational evidence

Protein change
AlphaMissense	0.1745	likely benign
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -5.69	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 81 kb · p 0.081 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.158% South Asian · 144/91,084 alleles

Filtering AF 0.137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.134% 2,156/1,614,202 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.493%	203
South Asiangrpmax	0.158%	633
European (non-Finnish)	0.133%	749
Remaining individualsnot 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 Jewishnot grpmax-eligible	0.00676%	14,802

Finnish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA1
Protein: p.Pro85Leu
Coding: c.254C>T
MANE Select: NM_005502
dbSNP: rs145183203
Type: single nucleotide variant
Location: chr9:104884475 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 85: a disulfide bond; a UniProt-annotated variant site (in fha1; alabama)

Full ABCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Tangier disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoalphalipoproteinemia, primary, 1

For Tangier disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

ABCA1 p.Pro85Ser Uncertain significance ★ ⚠ same residue
ABCA1 p.Pro85= Likely benign ★ same residue
ABCA1 c.5237+3A>C Likely pathogenic ★★ same condition
ABCA1 p.Arg2080Trp Likely pathogenic ★★ same condition
ABCA1 p.Arg587Trp Pathogenic/Likely pathogenic ★★ same condition
ABCA1 p.Asn1800His Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCA1 c.*2330A>T Uncertain significance ★★ same condition
ABCA1 c.*379C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca1-p-pro85leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown