Is ADCY3 p.Pro131= (c.393G>C) pathogenic?

ADCY3 p.Pro131= (c.393G>C) is classified Likely benign in ADCY3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-07-10). Very rare (popmax 0.00373%, nfe); Associated with ADCY3-related disorder.

What condition is associated with ADCY3 p.Pro131= (c.393G>C)?

ADCY3 p.Pro131= (c.393G>C) is associated with ADCY3-related disorder (ClinVar).

How common is ADCY3 p.Pro131= (c.393G>C) in the general population?

ADCY3 p.Pro131= (c.393G>C) is very rare (popmax 0.00373%, nfe) (gnomAD).

ADCY3 p.Pro131=

c.393G>C · VCV3351898

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Conditions

ADCY3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.5
Overall
CADD	0.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,180,030 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00297% 48/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,819
African / African-American	0.00267%	37,466
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,088

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: ADCY3
Protein: p.Pro131=
Coding: c.393G>C
MANE Select: NM_004036
Type: single nucleotide variant
Location: chr2:24918595 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.86

Full ADCY3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ADCY3-related disorder

Similar variants

ADCY3 p.Val195Met Uncertain significance ★★ ⚠ same condition
ADCY3 c.2496-13C>T Uncertain significance ★ same condition
ADCY3 p.Arg252Cys Uncertain significance ★ ⚠ same condition
ADCY3 p.Arg564His Uncertain significance ★ ⚠ same condition
ADCY3 p.Arg623Cys Uncertain significance ★ ⚠ same condition
ADCY3 p.Glu346Lys Uncertain significance ★ ⚠ same condition
ADCY3 p.Met461Ile Uncertain significance ★ ⚠ same condition
ADCY3 p.Thr738Met Uncertain significance ★ ⚠ same condition

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/adcy3-p-pro131 (accessed [today's date]).

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