Is ABCD4 p.Thr439= (c.1317G>A) pathogenic?

ABCD4 p.Thr439= (c.1317G>A) is classified Likely benign in ABCD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-22). Very rare (popmax 0.00223%, eas); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Thr439= (c.1317G>A)?

ABCD4 p.Thr439= (c.1317G>A) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Thr439= (c.1317G>A) in the general population?

ABCD4 p.Thr439= (c.1317G>A) is very rare (popmax 0.00223%, eas) (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.Thr439=

c.1317G>A · rs201586690 · VCV1125109

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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	0.037	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -5
Overall
CADD	3.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000743% 12/1,614,200 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asiangrpmax	0.00223%	44,890
Admixed American	0.00167%	60,024
African / African-American	0.00133%	75,034
European (non-Finnish)	0.000508%	196,674

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr439=
Coding: c.1317G>A
MANE Select: NM_005050
dbSNP: rs201586690
Type: single nucleotide variant
Location: chr14:74290301 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 439: 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.Thr439Met Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCD4 p.Thr439Arg 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

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-thr439 (accessed [today's date]).

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