Is ABCD4 c.1752+5C>T pathogenic?

ABCD4 c.1752+5C>T is classified Benign in ABCD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Low-frequency (popmax 4.16%, sas); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 c.1752+5C>T?

ABCD4 c.1752+5C>T is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 c.1752+5C>T in the general population?

ABCD4 c.1752+5C>T is low-frequency (popmax 4.16%, 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.

ABCD4 c.1752+5C>T

rs370270229 · VCV517093

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.16%, sas)

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	0.163	moderately benign-leaning
Splicing
Splice region	donor +5	donor splice region (+5, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.93	GERP 0.23, phastCons 0.001
Non-coding constraint	Z 1.27	1 kb window · o/e 0.87 · regional · uncalibrated
Overall
CADD	11.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.16% South Asian · 3,790/91,090 alleles

Filtering AF 4.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.01%

Overall 0.251% 4,045/1,614,044 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	4.16%	24
Remaining individualsnot grpmax-eligible	0.32%	313
Middle Eastern	0.297%	337
African / African-American	0.00666%	15,012
East Asian	0.00446%	22,441
European (non-Finnish)	0.00246%	40,690
Admixed American	0.00167%	60,014

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
Coding: c.1752+5C>T
MANE Select: NM_005050
dbSNP: rs370270229
Type: single nucleotide variant
Location: chr14:74286696 (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 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
ABCD4 c.719+6T>C 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-c-1752-plus-5c-t (accessed [today's date]).

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