Is ABCA2 p.Arg1362Trp (c.4084C>T) pathogenic?

ABCA2 p.Arg1362Trp (c.4084C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.083); Ultra-rare (popmax 0.067%, amr).

How common is ABCA2 p.Arg1362Trp (c.4084C>T) in the general population?

ABCA2 p.Arg1362Trp (c.4084C>T) is ultra-rare (popmax 0.067%, amr) (gnomAD).

What do computational predictors say about ABCA2 p.Arg1362Trp (c.4084C>T)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg1362Trp

c.4084C>T · VCV4071701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.067%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP -0.062, phastCons 0.002
Regional constraint	o/e 1.04	unconstrained · MANE · 1,453 bp · p 0.54 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1361W vs ClinVar R1362W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.067% Admixed American · 40/59,692 alleles

Filtering AF 0.0505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0448%

Overall 0.00441% 71/1,609,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.067%	1,492
African / African-American	0.0134%	7,484
East Asian	0.00895%	11,175
South Asian	0.00774%	12,913
European (non-Finnish)	0.000849%	117,844

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.Arg1362Trp
Coding: c.4084C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137014324 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 1362: 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.Arg1362_Thr1367del Uncertain significance ★★ same residue
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

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-arg1362trp (accessed [today's date]).

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