Is COASY p.Pro14Leu (c.41C>T) pathogenic?

COASY p.Pro14Leu (c.41C>T) is classified Uncertain significance in COASY (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-05). AlphaMissense: ambiguous (0.4717); Very rare (popmax 0.00127%, sas); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Pro14Leu (c.41C>T)?

COASY p.Pro14Leu (c.41C>T) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Pro14Leu (c.41C>T) in the general population?

COASY p.Pro14Leu (c.41C>T) is very rare (popmax 0.00127%, sas) (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.Pro14Leu (c.41C>T)?

AlphaMissense predicts ambiguous (score 0.4717) — an in-silico prediction, not a clinical call.

COASY p.Pro14Leu

c.41C>T · rs571068316 · VCV1992543

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, sas)

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
AlphaMissense	0.4717	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -11.56	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	28.7	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 0.00127% South Asian · 1/78,872 alleles

Overall 0.00131% 2/152,352 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00197%	50,740
South Asiangrpmax	0.00127%	78,872

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro14Leu
Coding: c.41C>T
MANE Select: NM_025233
dbSNP: rs571068316
Type: single nucleotide variant
Location: chr17:42562663 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51

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.Pro14Ala 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-pro14leu (accessed [today's date]).

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