Is COASY p.Arg503Trp (c.1507A>T) pathogenic?

COASY p.Arg503Trp (c.1507A>T) is classified Uncertain significance in COASY (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-01). AlphaMissense: ambiguous (0.5224); Very rare (popmax 0.000508%, nfe); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Arg503Trp (c.1507A>T)?

COASY p.Arg503Trp (c.1507A>T) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Arg503Trp (c.1507A>T) in the general population?

COASY p.Arg503Trp (c.1507A>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

How is COASY protein-associated neurodegeneration inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COASY p.Arg503Trp (c.1507A>T)?

AlphaMissense predicts ambiguous (score 0.5224) — an in-silico prediction, not a clinical call.

COASY p.Arg503Trp

c.1507A>T · rs756436403 · VCV1382900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
AlphaMissense	0.5224	ambiguous
REVEL	0.73	pathogenic-leaning
SaProt	LLR -15.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.22, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	24.6	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 0.000508% European (non-Finnish) · 6/1,180,034 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,926 alleles · very rare

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: COASY
Protein: p.Arg503Trp
Coding: c.1507A>T
MANE Select: NM_025233
dbSNP: rs756436403
Type: single nucleotide variant
Location: chr17:42565680 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 503: the dpck domain; a UniProt-annotated variant site (in nbia6; reduced protein abundance)

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

Disease context

neurodegeneration with brain iron accumulation 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COASY protein-associated neurodegeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COASY p.Arg503= Likely benign ★ same residue
COASY p.Arg503Met Uncertain significance ★ ⚠ same residue
COASY c.1486-3C>G Pathogenic/Likely pathogenic ★★ same condition
COASY p.Ala214Val Likely pathogenic ★★ ⚠ same condition
COASY p.Arg377Ter Pathogenic/Likely pathogenic ★★ same condition
COASY p.Arg499Cys Pathogenic ★★ same condition
COASY p.Gln523Ter Pathogenic ★★ same condition
COASY p.Ala206Ser 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/coasy-p-arg503trp (accessed [today's date]).

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