Is ACY1 p.Arg378Gln (c.1133G>A) pathogenic?

ACY1 p.Arg378Gln (c.1133G>A) is classified Uncertain significance in ACY1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-04). AlphaMissense: likely benign (0.178); Rare (popmax 0.202%, amr); Associated with aminoacylase 1 deficiency.

What condition is associated with ACY1 p.Arg378Gln (c.1133G>A)?

ACY1 p.Arg378Gln (c.1133G>A) is associated with aminoacylase 1 deficiency (ClinVar).

How common is ACY1 p.Arg378Gln (c.1133G>A) in the general population?

ACY1 p.Arg378Gln (c.1133G>A) is rare (popmax 0.202%, amr) (gnomAD).

How is Aminoacylase 1 deficiency inherited?

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

What do computational predictors say about ACY1 p.Arg378Gln (c.1133G>A)?

AlphaMissense predicts likely benign (score 0.178) — an in-silico prediction, not a clinical call.

ACY1 p.Arg378Gln

c.1133G>A · rs150480963 · VCV809490

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.178 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.202%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aminoacylase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.178	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.5	GERP 0.68, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,007 bp · p 0.014 · regional, not allelic
Overall
CADD	28.1	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 0.202% Admixed American · 121/59,996 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.00855% 138/1,614,004 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.202%	496
Middle Eastern	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.00439%	22,770
East Asian	0.00223%	44,886
African / African-American	0.00134%	74,900
European (non-Finnish)	0.000339%	295,008

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: ACY1
Protein: p.Arg378Gln
Coding: c.1133G>A
dbSNP: rs150480963
Type: single nucleotide variant
Location: chr3:51988981 (GRCh38)

Full ACY1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aminoacylase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aminoacylase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

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/acy1-p-arg378gln (accessed [today's date]).

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