Is ACY3 p.Arg8Trp (c.22C>T) pathogenic?

ACY3 p.Arg8Trp (c.22C>T) is classified Uncertain significance in ACY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.1046); Very rare (popmax 0.00733%, eas).

How common is ACY3 p.Arg8Trp (c.22C>T) in the general population?

ACY3 p.Arg8Trp (c.22C>T) is very rare (popmax 0.00733%, eas) (gnomAD).

What do computational predictors say about ACY3 p.Arg8Trp (c.22C>T)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

ACY3 p.Arg8Trp

c.22C>T · rs200922233 · VCV3143275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00733%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.7	GERP 0.11, phastCons 0.003
Regional constraint	o/e 0.99	unconstrained · MANE · 4,316 bp · p 0.86 · regional, not allelic
Overall
CADD	18.23	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 0.00733% East Asian · 3/40,942 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00026% 4/1,538,946 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00733%	13,647
European (non-Finnish)	8.77e-05%	1,139,903

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: ACY3
Protein: p.Arg8Trp
Coding: c.22C>T
MANE Select: NM_080658
dbSNP: rs200922233
Type: single nucleotide variant
Location: chr11:67647022 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.61
Residue 8: the 'hydrolytic domain' region; a UniProt-annotated variant site (in)

Full ACY3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACY3 p.Ala120Gly Uncertain significance ★ ⚠ same type
ACY3 p.Ala128Thr Uncertain significance ★ ⚠ same type
ACY3 p.Ala15Ser Uncertain significance ★ ⚠ same type
ACY3 p.Ala222Asp Uncertain significance ★ ⚠ same type
ACY3 p.Ala294Asp Uncertain significance ★ ⚠ same type
ACY3 p.Ala310Ser Uncertain significance ★ ⚠ same type
ACY3 p.Ala39Thr Uncertain significance ★ ⚠ same type
ACY3 p.Ala53Thr 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/acy3-p-arg8trp (accessed [today's date]).

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