Is ABCA5 p.Arg428Trp (c.1282C>T) pathogenic?

ABCA5 p.Arg428Trp (c.1282C>T) is classified Uncertain significance in ABCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.1942); Ultra-rare (popmax 0.0384%, amr).

How common is ABCA5 p.Arg428Trp (c.1282C>T) in the general population?

ABCA5 p.Arg428Trp (c.1282C>T) is ultra-rare (popmax 0.0384%, amr) (gnomAD).

What do computational predictors say about ABCA5 p.Arg428Trp (c.1282C>T)?

AlphaMissense predicts likely benign (score 0.1942) — an in-silico prediction, not a clinical call.

ABCA5 p.Arg428Trp

c.1282C>T · VCV3517523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1942	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.22 · regional, not allelic
Overall
CADD	25.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% Admixed American · 20/52,148 alleles

Filtering AF 0.0253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0212%

Overall 0.00309% 49/1,587,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0384%	2,607
Remaining individualsnot grpmax-eligible	0.00652%	15,339
East Asian	0.00453%	22,098
European (non-Finnish)	0.00188%	53,323
African / African-American	0.00137%	72,896

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: ABCA5
Protein: p.Arg428Trp
Coding: c.1282C>T
MANE Select: NM_172232
Type: single nucleotide variant
Location: chr17:69297345 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.12

Full ABCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA5 p.Arg428Gln Uncertain significance ★ ⚠ same residue
ABCA5 p.Ser288Phe Uncertain significance ★★ ⚠ same type
ABCA5 c.4765+3A>G Likely benign ★★ same type
ABCA5 p.Asn190Ser Likely benign ★★ ⚠ same type
ABCA5 p.Asn768Asp Benign ★★ same type
ABCA5 p.Asp817Tyr Likely benign ★★ ⚠ same type
ABCA5 p.Gly1159Arg Likely benign ★★ ⚠ same type
ABCA5 p.Gly128= Benign/Likely benign ★★ 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/abca5-p-arg428trp (accessed [today's date]).

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