Is ABCA2 p.Arg2146Trp (c.6436C>T) pathogenic?

ABCA2 p.Arg2146Trp (c.6436C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.1924); Ultra-rare (popmax 0.0407%, amr).

How common is ABCA2 p.Arg2146Trp (c.6436C>T) in the general population?

ABCA2 p.Arg2146Trp (c.6436C>T) is ultra-rare (popmax 0.0407%, amr) (gnomAD).

What do computational predictors say about ABCA2 p.Arg2146Trp (c.6436C>T)?

AlphaMissense predicts likely benign (score 0.1924) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg2146Trp

c.6436C>T · rs559341917 · VCV2523766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0407%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1924	likely benign
REVEL	0.651	pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP -2.7, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 3,800 bp · p 6.1e-23 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R2145W vs ClinVar R2146W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0407% Admixed American · 24/58,992 alleles

Filtering AF 0.028% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.00562% 90/1,601,368 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0407%	2,458
South Asian	0.01%	9,967
Remaining individualsnot grpmax-eligible	0.00484%	20,677
European (non-Finnish)	0.00442%	22,620
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,360
African / African-American	0.00134%	74,824

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: ABCA2
Protein: p.Arg2146Trp
Coding: c.6436C>T
MANE Select: NM_001606
dbSNP: rs559341917
Type: single nucleotide variant
Location: chr9:137010042 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 2146: the abc transporter 2 domain; a UniProt-annotated variant site (in idpogsa)

Full ABCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA2 p.Gln1370Ter Likely pathogenic ★★ same type
ABCA2 c.3883-3C>T Uncertain significance ★★ same type
ABCA2 p.Ala1357Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1620Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1645Val Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1715Ser Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2180Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2206Val Uncertain significance ★★ ⚠ 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/abca2-p-arg2146trp (accessed [today's date]).

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