Is ABCD3 p.Arg496Cys (c.1486C>T) pathogenic?

ABCD3 p.Arg496Cys (c.1486C>T) is classified Uncertain significance in ABCD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-21). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0329%, mid).

How common is ABCD3 p.Arg496Cys (c.1486C>T) in the general population?

ABCD3 p.Arg496Cys (c.1486C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ABCD3 p.Arg496Cys (c.1486C>T)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

ABCD3 p.Arg496Cys

c.1486C>T · rs1474170733 · VCV1917228

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -8.06	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 0.038	GERP 1.9, phastCons 0.04
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 0.00033 · regional, not allelic
Overall
CADD	20.2	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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00223% 36/1,613,466 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Finnishnot grpmax-eligible	0.00313%	31,984
European (non-Finnish)	0.00237%	42,135
Admixed American	0.00167%	59,934
Remaining individualsnot grpmax-eligible	0.0016%	62,462
African / African-American	0.00134%	74,826

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.Arg496Cys
Coding: c.1486C>T
MANE Select: NM_002858
dbSNP: rs1474170733
Type: single nucleotide variant
Location: chr1:94498804 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB
Residue 496: the abc transporter domain; a β-strand

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

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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-arg496cys (accessed [today's date]).

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