Is ACY3 p.Arg250Gln (c.749G>A) pathogenic?

ACY3 p.Arg250Gln (c.749G>A) is classified Likely benign in ACY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0647); Very rare (popmax 0.00659%, sas).

How common is ACY3 p.Arg250Gln (c.749G>A) in the general population?

ACY3 p.Arg250Gln (c.749G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about ACY3 p.Arg250Gln (c.749G>A)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

ACY3 p.Arg250Gln

c.749G>A · VCV3485847

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.8	GERP -3.4
Regional constraint	o/e 0.99	unconstrained · MANE · 4,316 bp · p 0.86 · regional, not allelic
Overall
CADD	2.053	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 0.00659% South Asian · 6/91,014 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00285% 46/1,613,086 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,169
Remaining individualsnot grpmax-eligible	0.0032%	31,224
European (non-Finnish)	0.00314%	31,887
African / African-American	0.00133%	74,928

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.Arg250Gln
Coding: c.749G>A
MANE Select: NM_080658
Type: single nucleotide variant
Location: chr11:67642935 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.61
Residue 250: 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-arg250gln (accessed [today's date]).

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