Is ABCD4 p.Pro526= (c.1578G>C) pathogenic?

ABCD4 p.Pro526= (c.1578G>C) is classified Likely benign in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). Very rare (popmax 8.48e-05%, nfe); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Pro526= (c.1578G>C)?

ABCD4 p.Pro526= (c.1578G>C) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Pro526= (c.1578G>C) in the general population?

ABCD4 p.Pro526= (c.1578G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Methylmalonic acidemia with homocystinuria inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCD4 p.Pro526=

c.1578G>C · VCV4718681

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.24	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP -10	GERP -5.3
Overall
CADD	0.159	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,518 alleles

Overall 6.85e-05% 1/1,460,800 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: ABCD4
Protein: p.Pro526=
Coding: c.1578G>C
MANE Select: NM_005050
Type: single nucleotide variant
Location: chr14:74287868 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 526: the abc transporter domain

Full ABCD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methylmalonic acidemia with homocystinuria, type cblJ — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Methylmalonic acidemia with homocystinuria (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

ABCD4 p.Pro526Leu Uncertain significance ★ ⚠ same residue
ABCD4 c.542+1G>T Pathogenic ★★ same condition
ABCD4 p.Arg432Gln Likely pathogenic ★★ same condition
ABCD4 p.Asn141Lys Pathogenic/Likely pathogenic ★★ same condition
ABCD4 p.Gln530Ter Pathogenic/Likely pathogenic ★★ same condition
ABCD4 p.Tyr176Ter Pathogenic/Likely pathogenic ★★ same condition
ABCD4 c.1028+5G>A Uncertain significance ★★ same condition
ABCD4 c.425+6C>T 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/abcd4-p-pro526 (accessed [today's date]).

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