Is ABCD4 p.Pro397Arg (c.1190C>G) pathogenic?

ABCD4 p.Pro397Arg (c.1190C>G) is classified Uncertain significance in ABCD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.7774); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCD4 p.Pro397Arg (c.1190C>G)?

ABCD4 p.Pro397Arg (c.1190C>G) is associated with Inborn genetic diseases, methylmalonic acidemia with homocystinuria, type cblJ (ClinVar).

How common is ABCD4 p.Pro397Arg (c.1190C>G) in the general population?

ABCD4 p.Pro397Arg (c.1190C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ABCD4 p.Pro397Arg (c.1190C>G)?

AlphaMissense predicts likely pathogenic (score 0.7774) — an in-silico prediction, not a clinical call.

ABCD4 p.Pro397Arg

c.1190C>G · rs749168282 · VCV1997709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7774	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -13.45	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	26.8	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 0.00333% Admixed American · 2/59,982 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,613,972 alleles · very rare exomes 5/1,461,878 · genomes 1/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,991
Finnishnot grpmax-eligible	0.00156%	64,020
European (non-Finnish)	0.000254%	393,345

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.Pro397Arg
Coding: c.1190C>G
MANE Select: NM_005050
dbSNP: rs749168282
Type: single nucleotide variant
Location: chr14:74290428 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 397: the abc transporter 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.Pro397His 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-pro397arg (accessed [today's date]).

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