Is ABCD4 p.Arg348Trp (c.1042C>T) pathogenic?

ABCD4 p.Arg348Trp (c.1042C>T) is classified Benign in ABCD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1459); Low-frequency (popmax 1.74%, sas); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Arg348Trp (c.1042C>T)?

ABCD4 p.Arg348Trp (c.1042C>T) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Arg348Trp (c.1042C>T) in the general population?

ABCD4 p.Arg348Trp (c.1042C>T) is low-frequency (popmax 1.74%, sas) (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.

What do computational predictors say about ABCD4 p.Arg348Trp (c.1042C>T)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

ABCD4 p.Arg348Trp

c.1042C>T · rs147795328 · VCV389017

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.74%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.49, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.74% South Asian · 1,588/91,074 alleles

Filtering AF 1.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.64%

Overall 0.138% 2,234/1,614,070 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.74%	57
Middle Eastern	0.561%	178
Remaining individualsnot grpmax-eligible	0.178%	563
African / African-American	0.0493%	2,028
Admixed American	0.0433%	2,308
European (non-Finnish)	0.0366%	2,732
Finnishnot grpmax-eligible	0.00469%	21,307
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg348Trp
Coding: c.1042C>T
MANE Select: NM_005050
dbSNP: rs147795328
Type: single nucleotide variant
Location: chr14:74292363 (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.Arg348Gln Benign/Likely benign ★★ same residue
ABCD4 p.Arg348Leu 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

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-arg348trp (accessed [today's date]).

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