Is ADCY3 p.Ser45Pro (c.133T>C) pathogenic?

ADCY3 p.Ser45Pro (c.133T>C) is classified Uncertain significance in ADCY3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADCY3 p.Ser45Pro (c.133T>C)?

ADCY3 p.Ser45Pro (c.133T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ADCY3 p.Ser45Pro (c.133T>C) in the general population?

ADCY3 p.Ser45Pro (c.133T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about ADCY3 p.Ser45Pro (c.133T>C)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

ADCY3 p.Ser45Pro

c.133T>C · rs1171056841 · VCV2634481

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.85	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 0.94	GERP -1.8, phastCons 0.016
Regional constraint	o/e 0.91	unconstrained · MANE · 561 bp · p 0.16 · regional, not allelic
Overall
CADD	16.14	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

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,032 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,214 alleles · very rare exomes 5/1,461,046 · genomes 2/152,168 · joint denominator

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.Ser45Pro
Coding: c.133T>C
MANE Select: NM_004036
dbSNP: rs1171056841
Type: single nucleotide variant
Location: chr2:24918855 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADCY3 p.Ala97Val Uncertain significance ★★ ⚠ same condition
ADCY3 p.Arg1041His Uncertain significance ★★ ⚠ same condition
ADCY3 p.Arg705Lys Uncertain significance ★★ ⚠ same condition
ADCY3 p.Asp474Asn Uncertain significance ★★ ⚠ same condition
ADCY3 p.Cys727Arg Uncertain significance ★★ ⚠ same condition
ADCY3 p.Glu60Asp Uncertain significance ★★ ⚠ same condition
ADCY3 p.Glu650Lys Uncertain significance ★★ ⚠ same condition
ADCY3 p.Gly1097Ser 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-ser45pro (accessed [today's date]).

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