Is ABCD4 p.Val172Ile (c.514G>A) pathogenic?

ABCD4 p.Val172Ile (c.514G>A) is classified Benign/Likely benign in ABCD4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.084); Common (popmax 22.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with methylmalonic acidemia with homocystinuria, type cblJ.

What condition is associated with ABCD4 p.Val172Ile (c.514G>A)?

ABCD4 p.Val172Ile (c.514G>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.Val172Ile (c.514G>A)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

ABCD4 p.Val172Ile

Q: How common is ABCD4 p.Val172Ile (c.514G>A) in the general population?

ABCD4 p.Val172Ile (c.514G>A) is common (popmax 22.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.514G>A · rs34992370 · VCV380499

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia with homocystinuria, type cblJ

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -4.5
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	0.194	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 22.9% African / African-American · 17,176/74,904 alleles

Filtering AF 22.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.5%

Overall 1.22% 19,692/1,613,968 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.9%	4
Remaining individualsnot grpmax-eligible	1.59%	63
Admixed American	1.49%	67
Middle Eastern	1.07%	93
European (non-Finnish)	0.0445%	2,248
South Asian	0.0428%	2,335
East Asian	0.00446%	22,435
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Val172Ile
Coding: c.514G>A
MANE Select: NM_005050
dbSNP: rs34992370
Type: single nucleotide variant
Location: chr14:74296361 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 172: a UniProt-annotated variant site (in); 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-val172ile (accessed [today's date]).

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