Is ACY3 p.Pro306Arg (c.917C>G) pathogenic?

ACY3 p.Pro306Arg (c.917C>G) is classified Uncertain significance in ACY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely benign (0.1671); Very rare (popmax 0.000169%, nfe).

How common is ACY3 p.Pro306Arg (c.917C>G) in the general population?

ACY3 p.Pro306Arg (c.917C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ACY3 p.Pro306Arg (c.917C>G)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

ACY3 p.Pro306Arg

c.917C>G · VCV4637234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.613	indeterminate
SaProt	LLR -13.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.70	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,316 bp · p 0.86 · regional, not allelic
Overall
CADD	22.4	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 0.000169% European (non-Finnish) · 2/1,180,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,844 alleles · very rare

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.Pro306Arg
Coding: c.917C>G
MANE Select: NM_080658
Type: single nucleotide variant
Location: chr11:67642767 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.61
Residue 306: the 'shielding domain' region

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-pro306arg (accessed [today's date]).

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