Is COASY p.Pro268Ser (c.802C>T) pathogenic?

COASY p.Pro268Ser (c.802C>T) is classified Conflicting classifications of pathogenicity in COASY (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.2045); Rare (popmax 0.556%, afr); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Pro268Ser (c.802C>T)?

COASY p.Pro268Ser (c.802C>T) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Pro268Ser (c.802C>T) in the general population?

COASY p.Pro268Ser (c.802C>T) is rare (popmax 0.556%, afr) (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.Pro268Ser (c.802C>T)?

AlphaMissense predicts likely benign (score 0.2045) — an in-silico prediction, not a clinical call.

COASY p.Pro268Ser

c.802C>T · rs143964295 · VCV767101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2045 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.556%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
AlphaMissense	0.2045	likely benign
REVEL	0.7	pathogenic-leaning
SaProt	LLR -10.31	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	24.5	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 0.556% African / African-American · 417/75,016 alleles

Filtering AF 0.512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.494%

Overall 0.0276% 446/1,614,090 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.556%	180
Admixed American	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.0192%	5,208
European (non-Finnish)	0.000169%	590,005

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.Pro268Ser
Coding: c.802C>T
MANE Select: NM_025233
dbSNP: rs143964295
Type: single nucleotide variant
Location: chr17:42564062 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 268: a UniProt-annotated variant site (in nbia6; reduced protein abundance); the 'phosphopantetheine adenylyltransferase domain' region

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.Pro268= Likely benign ★ same residue
COASY p.Pro268Leu 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-pro268ser (accessed [today's date]).

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