Is COASY p.Ala148= (c.444C>G) pathogenic?

COASY p.Ala148= (c.444C>G) is classified Likely benign in COASY (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Rare (popmax 0.33%, mid); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Ala148= (c.444C>G)?

COASY p.Ala148= (c.444C>G) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Ala148= (c.444C>G) in the general population?

COASY p.Ala148= (c.444C>G) is rare (popmax 0.33%, mid) (gnomAD).

How is COASY protein-associated neurodegeneration inherited?

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

COASY p.Ala148=

c.444C>G · rs142297801 · VCV774997

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.33%, mid)

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.099	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.78	GERP -5, phastCons 0.011
Overall
CADD	4.699	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.33% Middle Eastern · 20/6,062 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0208% 335/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.33%	303
Admixed American	0.115%	870
Remaining individualsnot grpmax-eligible	0.048%	2,084
European (non-Finnish)	0.0175%	5,701
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
African / African-American	0.00533%	18,764
South Asian	0.00329%	30,361

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.Ala148=
Coding: c.444C>G
MANE Select: NM_025233
dbSNP: rs142297801
Type: single nucleotide variant
Location: chr17:42563066 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 148: 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 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
COASY p.Ala395Thr 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-ala148 (accessed [today's date]).

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