Is ABCD4 c.719+2T>G pathogenic?

ABCD4 c.719+2T>G is classified Likely pathogenic in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-16). Absent from gnomAD v4.1; Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 c.719+2T>G?

ABCD4 c.719+2T>G is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 c.719+2T>G in the general population?

ABCD4 c.719+2T>G is absent from gnomAD v4.1 (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.719+2T>G

rs2082518811 · VCV976682

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.94	donor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.81	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Non-coding constraint	Z 2.11	1 kb window · o/e 0.86 · regional · uncalibrated
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCD4
Coding: c.719+2T>G
MANE Select: NM_005050
dbSNP: rs2082518811
Type: single nucleotide variant
Location: chr14:74295146 (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-719-plus-2t-g (accessed [today's date]).

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