Is ABCD4 p.Ser533fs (c.1597_1598del) pathogenic?

ABCD4 p.Ser533fs (c.15971598del) is classified Likely pathogenic in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-23). Very rare (popmax 0.00133%, afr); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with ABCD4 p.Ser533fs (c.1597_1598del)?

ABCD4 p.Ser533fs (c.1597_1598del) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is ABCD4 p.Ser533fs (c.1597_1598del) in the general population?

ABCD4 p.Ser533fs (c.1597_1598del) is very rare (popmax 0.00133%, 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.Ser533fs

c.1597_1598del · rs1390206641 · VCV2501162

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.23	GERP -4, phastCons 0.87
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,928 alleles

Overall 6.2e-05% 1/1,613,246 alleles · very rare exomes 0/1,461,002 · genomes 1/152,244 · joint denominator

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.Ser533fs
Coding: c.1597_1598del
MANE Select: NM_005050
dbSNP: rs1390206641
Type: Microsatellite
Location: chr14:74287848 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 533: the abc transporter domain

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

Disease context

methylmalonic aciduria and homocystinuria type cblC — 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.Ser416fs 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 c.1118+1G>A Likely pathogenic ★ same condition
ABCD4 p.Gln177Ter Pathogenic ★ same condition
ABCD4 p.Gly183_Trp184insTer Pathogenic ★ same condition
ABCD4 p.Tyr476fs Pathogenic ★ 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-ser533fs (accessed [today's date]).

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