Is ABCA2 p.Arg445Trp (c.1333C>T) pathogenic?

ABCA2 p.Arg445Trp (c.1333C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.8491); Ultra-rare (popmax 0.0332%, mid); Associated with intellectual developmental disorder with poor growth and with or without seizures or ataxia.

How common is ABCA2 p.Arg445Trp (c.1333C>T) in the general population?

ABCA2 p.Arg445Trp (c.1333C>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about ABCA2 p.Arg445Trp (c.1333C>T)?

AlphaMissense predicts likely pathogenic (score 0.8491) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg445Trp

Q: What condition is associated with ABCA2 p.Arg445Trp (c.1333C>T)?

ABCA2 p.Arg445Trp (c.1333C>T) is associated with intellectual developmental disorder with poor growth and with or without seizures or ataxia (ClinVar).

c.1333C>T · VCV4277744

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8491 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with poor growth and with or without seizures or ataxia

Computational evidence

Protein change
AlphaMissense	0.8491	likely pathogenic
REVEL	0.726	pathogenic-leaning
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 1,539 bp · p 6.3e-06 · regional, not allelic
Overall
CADD	27.7	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 R444W vs ClinVar R445W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,030 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000496% 8/1,612,328 alleles · ultra-rare exomes 8/1,459,994 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,015
East Asian	0.00223%	44,866
South Asian	0.0022%	45,523
European (non-Finnish)	0.000254%	393,253

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.Arg445Trp
Coding: c.1333C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137020428 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 444 UniProt numbering: a UniProt-annotated variant site (in idpogsa)

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

Disease context

intellectual developmental disorder with poor growth and with or without seizures or ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA2 p.Gln1370Ter Likely pathogenic ★★ same condition
ABCA2 p.Ala367Thr Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg114Gln Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1160His Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1383His Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1664Trp Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg954His Uncertain significance ★★ ⚠ same condition
ABCA2 p.Asn1755Lys 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/abca2-p-arg445trp (accessed [today's date]).

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