Is ABCA1 p.Arg219Lys (c.656G>A) pathogenic?

ABCA1 p.Arg219Lys (c.656G>A) is classified Benign in ABCA1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0723); Common (popmax 63.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with ABCA1 p.Arg219Lys (c.656G>A)?

ABCA1 p.Arg219Lys (c.656G>A) is associated with Cardiovascular phenotype, Tangier disease, hypoalphalipoproteinemia, primary, 1 (ClinVar).

What do computational predictors say about ABCA1 p.Arg219Lys (c.656G>A)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

ABCA1 p.Arg219Lys

Q: How common is ABCA1 p.Arg219Lys (c.656G>A) in the general population?

ABCA1 p.Arg219Lys (c.656G>A) is common (popmax 63.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.656G>A · rs2230806 · VCV9506

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 63.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.7	GERP -1.7
Regional constraint	o/e 0.95	unconstrained · MANE · 81 kb · p 0.081 · regional, not allelic
Overall
CADD	6.182	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 63.5% African / African-American · 47,609/74,940 alleles

Filtering AF 63.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 62.9%

Overall 30.2% 486,827/1,613,856 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	63.5%	2
East Asian	46.7%	2
Amishnot grpmax-eligible	44.7%	2
Middle Eastern	40.4%	2
South Asian	36.8%	3
Admixed American	33.3%	3
Remaining individualsnot grpmax-eligible	32.1%	3
Ashkenazi Jewishnot grpmax-eligible	28%	4
European (non-Finnish)	27.1%	4
Finnishnot grpmax-eligible	22.1%	5

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.Arg219Lys
Coding: c.656G>A
MANE Select: NM_005502
dbSNP: rs2230806
Type: single nucleotide variant
Location: chr9:104858586 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 219: an α-helix; a disulfide bond; a UniProt-annotated variant site (in)

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

Disease context

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

Also linked: Tangier disease hypoalphalipoproteinemia, primary, 1

Similar variants

ABCA1 p.Arg219= Likely benign ★ same residue
ABCA1 c.4175+1G>T Pathogenic/Likely pathogenic ★★ same condition
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 p.Thr940Met Pathogenic/Likely pathogenic ★★ same condition
ABCA1 c.3787+5C>A 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-arg219lys (accessed [today's date]).

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