Is ACY1 p.Cys331Arg (c.991T>C) pathogenic?

ACY1 p.Cys331Arg (c.991T>C) is classified Uncertain significance in ACY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.9489); Very rare (popmax 0.00133%, afr).

How common is ACY1 p.Cys331Arg (c.991T>C) in the general population?

ACY1 p.Cys331Arg (c.991T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACY1 p.Cys331Arg (c.991T>C)?

AlphaMissense predicts likely pathogenic (score 0.9489) — an in-silico prediction, not a clinical call.

ACY1 p.Cys331Arg

c.991T>C · rs996051231 · VCV1923982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9489	likely pathogenic · top 8% in ACY1
REVEL	0.407	indeterminate
SaProt	LLR -14.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,007 bp · p 0.014 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00133% African / African-American · 1/74,912 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,098 alleles · very rare exomes 3/1,461,894 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,912
European (non-Finnish)	0.000339%	295,011

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.Cys331Arg
Coding: c.991T>C
MANE Select: NM_000666
dbSNP: rs996051231
Type: single nucleotide variant
Location: chr3:51988593 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.55 · 1 PDB
Residue 331: 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.Pro266Thr Uncertain significance ★ ⚠ same type
ACY1 p.Ser406Ile 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-cys331arg (accessed [today's date]).

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