Is ABCA1 p.Arg1228Trp (c.3682C>T) pathogenic?

ABCA1 p.Arg1228Trp (c.3682C>T) is classified Likely benign in ABCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.3816); Very rare (popmax 0.00669%, eas).

How common is ABCA1 p.Arg1228Trp (c.3682C>T) in the general population?

ABCA1 p.Arg1228Trp (c.3682C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ABCA1 p.Arg1228Trp (c.3682C>T)?

AlphaMissense predicts ambiguous (score 0.3816) — an in-silico prediction, not a clinical call.

ABCA1 p.Arg1228Trp

c.3682C>T · VCV4775225

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3816	ambiguous
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.21, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 16 kb · p 0.021 · regional, not allelic
Overall
CADD	26.5	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 0.00669% East Asian · 3/44,864 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00109% 16/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
African / African-American	0.00133%	74,994
South Asian	0.0011%	91,086
European (non-Finnish)	0.000932%	107,273

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.Arg1228Trp
Coding: c.3682C>T
MANE Select: NM_005502
Type: single nucleotide variant
Location: chr9:104816199 (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

Similar variants

ABCA1 p.Arg1228= Benign ★★ same residue
ABCA1 p.Arg1228Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA1 p.Arg1228Gly Uncertain significance ★ ⚠ same residue
ABCA1 c.4175+1G>T Pathogenic/Likely pathogenic ★★ same type
ABCA1 c.4274+1G>A Likely pathogenic ★★ same type
ABCA1 c.5237+3A>C Likely pathogenic ★★ same type
ABCA1 p.Arg2080Trp Likely pathogenic ★★ same type
ABCA1 p.Arg557Ter Pathogenic/Likely pathogenic ★★ same type

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-arg1228trp (accessed [today's date]).

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