Is ABCD4 p.Ile166Thr (c.497T>C) pathogenic?

ABCD4 p.Ile166Thr (c.497T>C) is classified Likely benign in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). AlphaMissense: ambiguous (0.5119); Ultra-rare (popmax 0.0628%, afr); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Ile166Thr (c.497T>C)?

ABCD4 p.Ile166Thr (c.497T>C) is associated with methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Ile166Thr (c.497T>C) in the general population?

ABCD4 p.Ile166Thr (c.497T>C) is ultra-rare (popmax 0.0628%, afr) (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.Ile166Thr (c.497T>C)?

AlphaMissense predicts ambiguous (score 0.5119) — an in-silico prediction, not a clinical call.

ABCD4 p.Ile166Thr

c.497T>C · rs145669133 · VCV2858385

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0628%, afr)

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
AlphaMissense	0.5119	ambiguous
REVEL	0.562	indeterminate
SaProt	LLR -7.60	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	23.1	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 0.0628% African / African-American · 47/74,872 alleles

Filtering AF 0.0484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0434%

Overall 0.00347% 56/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0628%	1,593
Admixed American	0.01%	9,996
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Ile166Thr
Coding: c.497T>C
MANE Select: NM_005050
dbSNP: rs145669133
Type: single nucleotide variant
Location: chr14:74296378 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 166: the abc transmembrane type-1 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 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-ile166thr (accessed [today's date]).

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