Is ADCY10 p.Glu645Lys (c.1933G>A) pathogenic?

ADCY10 p.Glu645Lys (c.1933G>A) is classified Uncertain significance in ADCY10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: ambiguous (0.3669); Very rare (popmax 0.000508%, nfe); Associated with ADCY10-related disorder.

What condition is associated with ADCY10 p.Glu645Lys (c.1933G>A)?

ADCY10 p.Glu645Lys (c.1933G>A) is associated with ADCY10-related disorder (ClinVar).

How common is ADCY10 p.Glu645Lys (c.1933G>A) in the general population?

ADCY10 p.Glu645Lys (c.1933G>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about ADCY10 p.Glu645Lys (c.1933G>A)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

ADCY10 p.Glu645Lys

c.1933G>A · rs2525335470 · VCV2637351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

ADCY10-related disorder

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.592	indeterminate
SaProt	LLR -7.65	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 95 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	23.2	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 0.000508% European (non-Finnish) · 6/1,180,030 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,886 alleles · very rare

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: ADCY10
Protein: p.Glu645Lys
Coding: c.1933G>A
MANE Select: NM_018417
dbSNP: rs2525335470
Type: single nucleotide variant
Location: chr1:167856403 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 37 PDB

Full ADCY10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ADCY10-related disorder

Similar variants

ADCY10 p.Glu645Gly Uncertain significance ★ ⚠ same residue
ADCY10 p.Ala1278Asp Uncertain significance ★★ ⚠ same condition
ADCY10 c.1810-9T>G Likely benign same condition
ADCY10 c.293-20C>T Likely benign same condition
ADCY10 p.Leu71= Likely benign same condition
ADCY10 p.Ile525fs Likely pathogenic same condition
ADCY10 c.1139+6T>G Uncertain significance ★★ same type
ADCY10 c.253+4A>G 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/adcy10-p-glu645lys (accessed [today's date]).

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