Is ABCA1 p.Arg2080Trp (c.6238C>T) pathogenic?

ABCA1 p.Arg2080Trp (c.6238C>T) is classified Likely pathogenic in ABCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-23). AlphaMissense: likely pathogenic (0.9794); Very rare (popmax 0.000763%, nfe); Associated with Tangier disease.

What condition is associated with ABCA1 p.Arg2080Trp (c.6238C>T)?

ABCA1 p.Arg2080Trp (c.6238C>T) is associated with Tangier disease (ClinVar).

How common is ABCA1 p.Arg2080Trp (c.6238C>T) in the general population?

ABCA1 p.Arg2080Trp (c.6238C>T) is very rare (popmax 0.000763%, nfe) (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.Arg2080Trp (c.6238C>T)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

ABCA1 p.Arg2080Trp

c.6238C>T · rs780321144 · VCV3078691

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tangier disease

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic ✓ concordant with ClinVar
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -12.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 22 kb · p 3.8e-10 · regional, not allelic
Overall
CADD	32.0	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 0.000763% European (non-Finnish) · 9/1,179,980 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,896 alleles · very rare

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.Arg2080Trp
Coding: c.6238C>T
MANE Select: NM_005502
dbSNP: rs780321144
Type: single nucleotide variant
Location: chr9:104786943 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 2080: the abc transporter 2 domain; an α-helix

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

For Tangier disease (Orphanet):

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

Similar variants

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
ABCA1 p.Arg999Cys Uncertain significance ★★ ⚠ same condition
ABCA1 p.Cys23Tyr 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-arg2080trp (accessed [today's date]).

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