Is COASY p.Leu71Phe (c.211C>T) pathogenic?

COASY p.Leu71Phe (c.211C>T) is classified Uncertain significance in COASY (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-11). AlphaMissense: likely benign (0.0593); Ultra-rare (popmax 0.0291%, nfe); Associated with neurodegeneration with brain iron accumulation 6.

What condition is associated with COASY p.Leu71Phe (c.211C>T)?

COASY p.Leu71Phe (c.211C>T) is associated with neurodegeneration with brain iron accumulation 6 (ClinVar).

How common is COASY p.Leu71Phe (c.211C>T) in the general population?

COASY p.Leu71Phe (c.211C>T) is ultra-rare (popmax 0.0291%, 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.Leu71Phe (c.211C>T)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

COASY p.Leu71Phe

c.211C>T · rs141350621 · VCV1356970

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0291%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodegeneration with brain iron accumulation 6

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -4.7, phastCons 0.022
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	11.82	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0291% European (non-Finnish) · 343/1,179,592 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0255%

Overall 0.0218% 352/1,613,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0291%	3,439
Remaining individualsnot grpmax-eligible	0.00801%	12,491
African / African-American	0.00534%	18,732

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.Leu71Phe
Coding: c.211C>T
MANE Select: NM_025233
dbSNP: rs141350621
Type: single nucleotide variant
Location: chr17:42562833 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 71: 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.Leu71Ile Uncertain significance ★★ ⚠ same residue
COASY p.Leu71= Likely benign ★ 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-leu71phe (accessed [today's date]).

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