Is ABCD3 c.684+228G>A pathogenic?

ABCD3 c.684+228G>A is classified Likely benign in ABCD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). Very rare (popmax 0.00338%, amr); Associated with congenital bile acid synthesis defect 5.

What condition is associated with ABCD3 c.684+228G>A?

ABCD3 c.684+228G>A is associated with congenital bile acid synthesis defect 5 (ClinVar).

How common is ABCD3 c.684+228G>A in the general population?

ABCD3 c.684+228G>A is very rare (popmax 0.00338%, amr) (gnomAD).

ABCD3 c.684+228G>A

rs763228210 · VCV2921016

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Conditions

congenital bile acid synthesis defect 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +228	deep intronic (+228 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -4, phastCons 0.99
Non-coding constraint	Z 2.01	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	2.677	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00338% Admixed American · 2/59,240 alleles

Filtering AF 0.00056% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000138% 2/1,446,046 alleles · very rare

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: ABCD3
Coding: c.684+228G>A
MANE Select: NM_002858
dbSNP: rs763228210
Type: single nucleotide variant
Location: chr1:94478543 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB

Full ABCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital bile acid synthesis defect 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCD3 c.1846-31C>G Benign ★★ same condition
ABCD3 p.Gly52Val Benign ★★ same condition
ABCD3 p.Lys54= Benign ★★ same condition
ABCD3 c.1903-573_*1108del Pathogenic same condition
ABCD3 p.Ala131Thr Uncertain significance ★★ ⚠ same type
ABCD3 p.Ala3Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Arg496Cys Uncertain significance ★★ ⚠ same type
ABCD3 p.Asn12Tyr 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/abcd3-c-684-plus-228g-a (accessed [today's date]).

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