Is ABCD4 p.Thr341= (c.1023G>A) pathogenic?

ABCD4 p.Thr341= (c.1023G>A) is classified Benign/Likely benign in ABCD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.35%, afr); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Thr341= (c.1023G>A)?

ABCD4 p.Thr341= (c.1023G>A) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Thr341= (c.1023G>A) in the general population?

ABCD4 p.Thr341= (c.1023G>A) is low-frequency (popmax 1.35%, 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.Thr341=

c.1023G>A · rs35522023 · VCV382060

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.35%, afr)

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -5
Overall
CADD	3.922	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.35% African / African-American · 1,015/75,032 alleles

Filtering AF 1.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.26%

Overall 0.0794% 1,282/1,613,836 alleles · low-frequency exomes 731/1,461,562 · genomes 551/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.35%	74
Remaining individualsnot grpmax-eligible	0.162%	619
Middle Eastern	0.099%	1,010
Admixed American	0.0883%	1,132
East Asian	0.0669%	1,496
South Asian	0.0417%	2,396
European (non-Finnish)	0.00331%	30,254

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.Thr341=
Coding: c.1023G>A
MANE Select: NM_005050
dbSNP: rs35522023
Type: single nucleotide variant
Location: chr14:74292556 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB

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.Thr341Met 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-thr341 (accessed [today's date]).

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