Is ABCD4 p.Arg125Gln (c.374G>A) pathogenic?

ABCD4 p.Arg125Gln (c.374G>A) is classified Likely benign in ABCD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0704); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with ABCD4 p.Arg125Gln (c.374G>A)?

ABCD4 p.Arg125Gln (c.374G>A) is associated with Inborn genetic diseases, methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Arg125Gln (c.374G>A) in the general population?

ABCD4 p.Arg125Gln (c.374G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ABCD4 p.Arg125Gln (c.374G>A)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

ABCD4 p.Arg125Gln

c.374G>A · rs368694663 · VCV947229

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -2.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.019	GERP -3.1, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	18.31	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00508% 82/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00891%	11,224
Remaining individualsnot grpmax-eligible	0.008%	12,496
Admixed American	0.00667%	14,985
European (non-Finnish)	0.00525%	19,032
South Asian	0.00439%	22,766
African / African-American	0.00267%	37,443

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.Arg125Gln
Coding: c.374G>A
MANE Select: NM_005050
dbSNP: rs368694663
Type: single nucleotide variant
Location: chr14:74297981 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 125: the abc transmembrane type-1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylmalonic acidemia with homocystinuria, type cblJ

Similar variants

ABCD4 p.Arg125fs Pathogenic ★ 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-arg125gln (accessed [today's date]).

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