Is ABCD3 p.Pro425Leu (c.1274C>T) pathogenic?

ABCD3 p.Pro425Leu (c.1274C>T) is classified Uncertain significance in ABCD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1713); Ultra-rare (popmax 0.0584%, amr).

How common is ABCD3 p.Pro425Leu (c.1274C>T) in the general population?

ABCD3 p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0584%, amr) (gnomAD).

What do computational predictors say about ABCD3 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.1713) — an in-silico prediction, not a clinical call.

ABCD3 p.Pro425Leu

c.1274C>T · rs148848670 · VCV2514650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0584%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1713	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 0.00033 · regional, not allelic
Overall
CADD	21.2	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 0.0584% Admixed American · 35/59,942 alleles

Filtering AF 0.0431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00874% 141/1,612,908 alleles · ultra-rare exomes 116/1,461,042 · genomes 25/151,866 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0584%	1,713
Middle Eastern	0.0494%	2,023
Remaining individualsnot grpmax-eligible	0.0208%	4,804
European (non-Finnish)	0.00721%	13,874
African / African-American	0.00669%	14,958

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.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_002858
dbSNP: rs148848670
Type: single nucleotide variant
Location: chr1:94489927 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB

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

Similar variants

ABCD3 p.Pro425Ser Uncertain significance ★★ ⚠ same residue
ABCD3 p.Ala131Thr Uncertain significance ★★ ⚠ same type
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.Leu23Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu45Val 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-pro425leu (accessed [today's date]).

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