Is ABCD4 p.Glu368Lys (c.1102G>A) pathogenic?

ABCD4 p.Glu368Lys (c.1102G>A) is classified Benign/Likely benign in ABCD4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0854); Common (popmax 52.8%, mid) — too common for a highly-penetrant pathogenic allele; Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Glu368Lys (c.1102G>A)?

ABCD4 p.Glu368Lys (c.1102G>A) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

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.Glu368Lys (c.1102G>A)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

ABCD4 p.Glu368Lys

Q: How common is ABCD4 p.Glu368Lys (c.1102G>A) in the general population?

ABCD4 p.Glu368Lys (c.1102G>A) is common (popmax 52.8%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1102G>A · rs3742801 · VCV259619

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 52.8%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -7.04	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 0.41	GERP -0.55, phastCons 0.026
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	16.7	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 52.8% Middle Eastern · 3,199/6,062 alleles

Filtering AF 51.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.6%

Overall 34.9% 562,383/1,613,546 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	52.8%	2
Amishnot grpmax-eligible	46.7%	2
Ashkenazi Jewishnot grpmax-eligible	44.4%	2
South Asian	37%	3
European (non-Finnish)	36.4%	3
Remaining individualsnot grpmax-eligible	36%	3
Finnishnot grpmax-eligible	31.3%	3
Admixed American	25%	4
East Asian	24.3%	4
African / African-American	18.8%	5

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.Glu368Lys
Coding: c.1102G>A
MANE Select: NM_005050
dbSNP: rs3742801
Type: single nucleotide variant
Location: chr14:74292303 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 368: a UniProt-annotated variant site (in)

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-p-glu368lys (accessed [today's date]).

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