Is ABCA5 p.Arg682Lys (c.2045G>A) pathogenic?

ABCA5 p.Arg682Lys (c.2045G>A) is classified Uncertain significance in ABCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.5762); Ultra-rare (popmax 0.0369%, afr).

How common is ABCA5 p.Arg682Lys (c.2045G>A) in the general population?

ABCA5 p.Arg682Lys (c.2045G>A) is ultra-rare (popmax 0.0369%, afr) (gnomAD).

What do computational predictors say about ABCA5 p.Arg682Lys (c.2045G>A)?

AlphaMissense predicts likely pathogenic (score 0.5762) — an in-silico prediction, not a clinical call.

ABCA5 p.Arg682Lys

c.2045G>A · rs372894277 · VCV3104230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5762	likely pathogenic
REVEL	0.684	pathogenic-leaning
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.59	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.22 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0369% African / African-American · 27/73,096 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.00182% 29/1,589,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0369%	2,707
Admixed American	0.0039%	25,669

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.Arg682Lys
Coding: c.2045G>A
MANE Select: NM_172232
dbSNP: rs372894277
Type: single nucleotide variant
Location: chr17:69286308 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.12
Residue 682: the abc transporter 1 domain

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

Similar variants

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
ABCA5 p.Ile1173Val 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-arg682lys (accessed [today's date]).

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