Is ACY3 p.Val14Met (c.40G>A) pathogenic?

ACY3 p.Val14Met (c.40G>A) is classified Uncertain significance in ACY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6576); Ultra-rare (popmax 0.0169%, mid).

How common is ACY3 p.Val14Met (c.40G>A) in the general population?

ACY3 p.Val14Met (c.40G>A) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about ACY3 p.Val14Met (c.40G>A)?

AlphaMissense predicts likely pathogenic (score 0.6576) — an in-silico prediction, not a clinical call.

ACY3 p.Val14Met

c.40G>A · VCV3485834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6576	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -12.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.52	GERP 1.6, phastCons 0.002
Regional constraint	o/e 0.99	unconstrained · MANE · 4,316 bp · p 0.86 · regional, not allelic
Overall
CADD	21.6	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 0.0169% Middle Eastern · 1/5,922 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00341%

Overall 0.00174% 27/1,555,336 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,922
South Asian	0.00938%	10,658
African / African-American	0.00678%	14,738
East Asian	0.0048%	20,816
European (non-Finnish)	0.000958%	104,403

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.Val14Met
Coding: c.40G>A
MANE Select: NM_080658
Type: single nucleotide variant
Location: chr11:67647004 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.61
Residue 14: the 'hydrolytic 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-val14met (accessed [today's date]).

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