Is ABCA1 p.Arg666Trp (c.1996C>T) pathogenic?

ABCA1 p.Arg666Trp (c.1996C>T) is classified Conflicting classifications of pathogenicity in ABCA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.7671); Ultra-rare (popmax 0.0164%, mid); Associated with Tangier disease.

What condition is associated with ABCA1 p.Arg666Trp (c.1996C>T)?

ABCA1 p.Arg666Trp (c.1996C>T) is associated with Tangier disease, hypoalphalipoproteinemia, primary, 1 (ClinVar).

How common is ABCA1 p.Arg666Trp (c.1996C>T) in the general population?

ABCA1 p.Arg666Trp (c.1996C>T) is ultra-rare (popmax 0.0164%, mid) (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.Arg666Trp (c.1996C>T)?

AlphaMissense predicts likely pathogenic (score 0.7671) — an in-silico prediction, not a clinical call.

ABCA1 p.Arg666Trp

c.1996C>T · rs201599169 · VCV364439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tangier disease

Computational evidence

Protein change
AlphaMissense	0.7671	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -12.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.88, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 81 kb · p 0.081 · regional, not allelic
Overall
CADD	27.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00254% 41/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00769%	13,011
Admixed American	0.00667%	14,998
East Asian	0.00223%	44,906
European (non-Finnish)	0.0022%	45,386
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,926

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.Arg666Trp
Coding: c.1996C>T
MANE Select: NM_005502
dbSNP: rs201599169
Type: single nucleotide variant
Location: chr9:104829035 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB

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.Arg666Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA1 p.Arg666= 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-arg666trp (accessed [today's date]).

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