Is ACY1 p.Ser406Ile (c.1217G>T) pathogenic?

ACY1 p.Ser406Ile (c.1217G>T) is classified Uncertain significance in ACY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.1346); Absent from gnomAD v4.1.

How common is ACY1 p.Ser406Ile (c.1217G>T) in the general population?

ACY1 p.Ser406Ile (c.1217G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACY1 p.Ser406Ile (c.1217G>T)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

ACY1 p.Ser406Ile

c.1217G>T · rs1194568745 · VCV2008461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -9.47	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 2.2	GERP -3.6, phastCons 0.045
Regional constraint	o/e 0.89	unconstrained · MANE · 5,007 bp · p 0.014 · regional, not allelic
Overall
CADD	13.79	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACY1
Protein: p.Ser406Ile
Coding: c.1217G>T
MANE Select: NM_000666
dbSNP: rs1194568745
Type: single nucleotide variant
Location: chr3:51989065 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.55 · 1 PDB
Residue 406: an α-helix

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

Similar variants

ACY1 p.Arg109Gly Uncertain significance ★★ ⚠ same type
ACY1 p.Arg393His Benign/Likely benign ★★ same type
ACY1 p.Ala326Gly Uncertain significance ★ ⚠ same type
ACY1 p.Arg350His Uncertain significance ★ ⚠ same type
ACY1 p.Cys331Arg Uncertain significance ★ ⚠ same type
ACY1 p.Pro266Thr Uncertain significance ★ ⚠ same type
ACY1 c.1002-13C>G Likely benign ★ same type
ACY1 c.708-7A>T Likely benign ★ 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/acy1-p-ser406ile (accessed [today's date]).

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