Is ABCD4 p.Ala128= (c.384G>A) pathogenic?

ABCD4 p.Ala128= (c.384G>A) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). Ultra-rare (popmax 0.0214%, afr); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Ala128= (c.384G>A)?

ABCD4 p.Ala128= (c.384G>A) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Ala128= (c.384G>A) in the general population?

ABCD4 p.Ala128= (c.384G>A) is ultra-rare (popmax 0.0214%, afr) (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.Ala128=

c.384G>A · rs376619713 · VCV2162590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.243	benign-leaning
Splicing
SpliceAI	Δ0.45	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.042	GERP 0.13, phastCons 0.81
Overall
CADD	15.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% African / African-American · 16/74,910 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00198% 32/1,613,894 alleles · ultra-rare exomes 19/1,461,734 · genomes 13/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,682
South Asian	0.00549%	18,214
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.000763%	131,109

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.Ala128=
Coding: c.384G>A
MANE Select: NM_005050
dbSNP: rs376619713
Type: single nucleotide variant
Location: chr14:74297971 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 128: the abc transmembrane type-1 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.Ala128Val Benign/Likely benign ★★ 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-ala128 (accessed [today's date]).

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