Is ABCA2 p.Arg1117Trp (c.3349C>T) pathogenic?

ABCA2 p.Arg1117Trp (c.3349C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-28). AlphaMissense: likely pathogenic (0.788); Ultra-rare (popmax 0.0165%, mid).

How common is ABCA2 p.Arg1117Trp (c.3349C>T) in the general population?

ABCA2 p.Arg1117Trp (c.3349C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCA2 p.Arg1117Trp (c.3349C>T)?

AlphaMissense predicts likely pathogenic (score 0.788) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg1117Trp

c.3349C>T · rs1195370052 · VCV2601950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.788	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -16.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.18, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 914 bp · p 3.8e-13 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R1116W vs ClinVar R1117W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,610,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.00134%	74,906
European (non-Finnish)	0.000255%	392,889

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.Arg1117Trp
Coding: c.3349C>T
MANE Select: NM_001606
dbSNP: rs1195370052
Type: single nucleotide variant
Location: chr9:137015840 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 1117: the abc transporter 1 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-arg1117trp (accessed [today's date]).

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