Is ABCD4 p.Asn141Lys (c.423C>G) pathogenic?

ABCD4 p.Asn141Lys (c.423C>G) is classified Pathogenic/Likely pathogenic in ABCD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.9972); Ultra-rare (popmax 0.0111%, eas); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with ABCD4 p.Asn141Lys (c.423C>G)?

ABCD4 p.Asn141Lys (c.423C>G) is associated with methylmalonic aciduria and homocystinuria type cblC, methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Asn141Lys (c.423C>G) in the general population?

ABCD4 p.Asn141Lys (c.423C>G) is ultra-rare (popmax 0.0111%, 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.

What do computational predictors say about ABCD4 p.Asn141Lys (c.423C>G)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

ABCD4 p.Asn141Lys

c.423C>G · rs776529140 · VCV1343599

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic ✓ concordant with ClinVar · top 1% in ABCD4
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.98, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	26.4	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 0.0111% East Asian · 5/44,888 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000372% 6/1,613,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,978
Remaining individualsnot grpmax-eligible	0.0016%	62,402

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.Asn141Lys
Coding: c.423C>G
MANE Select: NM_005050
dbSNP: rs776529140
Type: single nucleotide variant
Location: chr14:74297932 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 141: the abc transmembrane type-1 domain; a UniProt-annotated variant site (in mahcj; does not affect atpase activity. loss of cobalamin transport activity. decreases interaction with lmbd1. does not affect lysosomal subcellular location)

Full ABCD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methylmalonic aciduria and homocystinuria type cblC — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylmalonic acidemia with homocystinuria, type cblJ

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.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
ABCD4 p.Ala507Glu 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-asn141lys (accessed [today's date]).

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