Is ABCA1 p.Thr774Pro (c.2320A>C) pathogenic?

ABCA1 p.Thr774Pro (c.2320A>C) is classified Conflicting classifications of pathogenicity in ABCA1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0535); Rare (popmax 0.44%, amr); Associated with Tangier disease.

What condition is associated with ABCA1 p.Thr774Pro (c.2320A>C)?

ABCA1 p.Thr774Pro (c.2320A>C) is associated with Tangier disease, hypoalphalipoproteinemia, primary, 1 (ClinVar).

How common is ABCA1 p.Thr774Pro (c.2320A>C) in the general population?

ABCA1 p.Thr774Pro (c.2320A>C) is rare (popmax 0.44%, amr) (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.Thr774Pro (c.2320A>C)?

AlphaMissense predicts likely benign (score 0.0535) — an in-silico prediction, not a clinical call.

ABCA1 p.Thr774Pro

c.2320A>C · rs35819696 · VCV364431

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0535 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.44%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tangier disease

Computational evidence

Protein change
AlphaMissense	0.0535	likely benign
REVEL	0.377	indeterminate
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -4.2, phastCons 0.96
Regional constraint	o/e 0.95	unconstrained · MANE · 81 kb · p 0.081 · regional, not allelic
Overall
CADD	15.54	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 0.44% Admixed American · 264/60,022 alleles

Filtering AF 0.396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.388%

Overall 0.33% 5,323/1,613,942 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.44%	227
European (non-Finnish)	0.402%	249
Remaining individualsnot grpmax-eligible	0.322%	311
Middle Eastern	0.185%	542
African / African-American	0.0786%	1,272
South Asian	0.0373%	2,679
Finnishnot grpmax-eligible	0.0188%	5,329
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804

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.Thr774Pro
Coding: c.2320A>C
MANE Select: NM_005502
dbSNP: rs35819696
Type: single nucleotide variant
Location: chr9:104826965 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 774: an α-helix; a UniProt-annotated variant site (in); a UniProt-annotated variant site (sequence variant)

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 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
ABCA1 p.Arg126Cys Uncertain significance ★★ ⚠ same condition
ABCA1 p.Arg1342Trp 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-thr774pro (accessed [today's date]).

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