Is COASY p.Val407Ala (c.1220T>C) pathogenic?

COASY p.Val407Ala (c.1220T>C) is classified Uncertain significance in COASY (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.1393); Very rare (popmax 0.000255%, nfe); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Val407Ala (c.1220T>C)?

COASY p.Val407Ala (c.1220T>C) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Val407Ala (c.1220T>C) in the general population?

COASY p.Val407Ala (c.1220T>C) is very rare (popmax 0.000255%, 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.Val407Ala (c.1220T>C)?

AlphaMissense predicts likely benign (score 0.1393) — an in-silico prediction, not a clinical call.

COASY p.Val407Ala

c.1220T>C · rs1567905480 · VCV1974368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
AlphaMissense	0.1393	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -11.35	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	27.8	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 0.000255% European (non-Finnish) · 3/1,175,764 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,454,726 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.Val407Ala
Coding: c.1220T>C
MANE Select: NM_025233
dbSNP: rs1567905480
Type: single nucleotide variant
Location: chr17:42564881 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 407: 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.Val407Leu 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
COASY p.Ala311Val 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-val407ala (accessed [today's date]).

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