Is ABCD3 p.Leu23Val (c.67C>G) pathogenic?

ABCD3 p.Leu23Val (c.67C>G) is classified Uncertain significance in ABCD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-20). AlphaMissense: likely benign (0.064); Very rare (popmax 0.00636%, nfe).

How common is ABCD3 p.Leu23Val (c.67C>G) in the general population?

ABCD3 p.Leu23Val (c.67C>G) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about ABCD3 p.Leu23Val (c.67C>G)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

ABCD3 p.Leu23Val

c.67C>G · rs747232088 · VCV2896024

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.66, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 46 kb · p 0.19 · regional, not allelic
Overall
CADD	19.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00636% European (non-Finnish) · 75/1,179,218 alleles

Filtering AF 0.0052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00492% 79/1,604,934 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,723
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,526
Remaining individualsnot grpmax-eligible	0.00321%	31,126
Admixed American	0.00167%	59,888

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: ABCD3
Protein: p.Leu23Val
Coding: c.67C>G
MANE Select: NM_002858
dbSNP: rs747232088
Type: single nucleotide variant
Location: chr1:94418545 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB
Residue 23: the 'interaction with pex19' region

Full ABCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ABCD3 p.Ala3Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Arg496Cys Uncertain significance ★★ ⚠ same type
ABCD3 p.Asn12Tyr Uncertain significance ★★ ⚠ same type
ABCD3 p.Ile225Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu45Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Pro425Leu Uncertain significance ★★ ⚠ same type
ABCD3 p.Pro425Ser Uncertain significance ★★ ⚠ same type

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/abcd3-p-leu23val (accessed [today's date]).

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