Is COASY p.Arg394Trp (c.1180C>T) pathogenic?

COASY p.Arg394Trp (c.1180C>T) is classified Uncertain significance in COASY (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-29). AlphaMissense: likely benign (0.1176); Very rare (popmax 0.00375%, amr).

How common is COASY p.Arg394Trp (c.1180C>T) in the general population?

COASY p.Arg394Trp (c.1180C>T) is very rare (popmax 0.00375%, amr) (gnomAD).

What do computational predictors say about COASY p.Arg394Trp (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

COASY p.Arg394Trp

c.1180C>T · VCV4231486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00375%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -10.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,342 bp · p 0.88 · regional, not allelic
Overall
CADD	27.0	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 0.00375% Admixed American · 2/53,312 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000842%

Overall 0.00146% 23/1,575,778 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00375%	26,656
European (non-Finnish)	0.00163%	61,211
Finnishnot grpmax-eligible	0.0016%	62,394
South Asian	0.00118%	85,022

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.Arg394Trp
Coding: c.1180C>T
MANE Select: NM_025233
Type: single nucleotide variant
Location: chr17:42564841 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.51
Residue 394: 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

Similar variants

COASY p.Arg394Gln Uncertain significance ★ ⚠ same residue
COASY c.1486-3C>G Pathogenic/Likely pathogenic ★★ same type
COASY p.Ala214Val Likely pathogenic ★★ ⚠ same type
COASY p.Arg377Ter Pathogenic/Likely pathogenic ★★ same type
COASY p.Arg499Cys Pathogenic ★★ same type
COASY p.Gln523Ter Pathogenic ★★ same type
COASY p.Ala206Ser Uncertain significance ★★ ⚠ same type
COASY p.Ala311Val Uncertain significance ★★ ⚠ same type

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-arg394trp (accessed [today's date]).

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