Is ABCD4 p.Ala545Thr (c.1633G>A) pathogenic?

ABCD4 p.Ala545Thr (c.1633G>A) is classified Uncertain significance in ABCD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-06-05). AlphaMissense: likely pathogenic (0.5962); Ultra-rare (popmax 0.0329%, mid); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Ala545Thr (c.1633G>A)?

ABCD4 p.Ala545Thr (c.1633G>A) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Ala545Thr (c.1633G>A) in the general population?

ABCD4 p.Ala545Thr (c.1633G>A) is ultra-rare (popmax 0.0329%, mid) (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.Ala545Thr (c.1633G>A)?

AlphaMissense predicts likely pathogenic (score 0.5962) — an in-silico prediction, not a clinical call.

ABCD4 p.Ala545Thr

c.1633G>A · rs754370477 · VCV934796

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
AlphaMissense	0.5962	likely pathogenic
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,076 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00124% 20/1,610,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,038
Remaining individualsnot grpmax-eligible	0.00481%	20,785
African / African-American	0.00401%	24,940
East Asian	0.00224%	44,742
South Asian	0.00221%	45,192
Admixed American	0.00167%	59,702
European (non-Finnish)	0.000679%	147,328

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.Ala545Thr
Coding: c.1633G>A
MANE Select: NM_005050
dbSNP: rs754370477
Type: single nucleotide variant
Location: chr14:74287813 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 545: the abc transporter domain

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.Ala545Ser Uncertain significance ★ ⚠ 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
ABCD4 c.425+6C>T 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-ala545thr (accessed [today's date]).

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