Is ADCY2 p.Cys654Arg (c.1960T>C) pathogenic?

ADCY2 p.Cys654Arg (c.1960T>C) is classified Uncertain significance in ADCY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1332); Very rare (popmax 0.00805%, nfe).

How common is ADCY2 p.Cys654Arg (c.1960T>C) in the general population?

ADCY2 p.Cys654Arg (c.1960T>C) is very rare (popmax 0.00805%, nfe) (gnomAD).

What do computational predictors say about ADCY2 p.Cys654Arg (c.1960T>C)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

ADCY2 p.Cys654Arg

c.1960T>C · VCV4235082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00805%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 46 kb · p 0.11 · regional, not allelic
Overall
CADD	23.1	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 0.00805% European (non-Finnish) · 95/1,179,804 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00625%

Overall 0.00626% 101/1,613,540 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00805%	12,419
Remaining individualsnot grpmax-eligible	0.008%	12,493
African / African-American	0.00134%	74,898

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: ADCY2
Protein: p.Cys654Arg
Coding: c.1960T>C
MANE Select: NM_020546
Type: single nucleotide variant
Location: chr5:7757452 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.91

Full ADCY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADCY2 p.Arg842Gln Uncertain significance ★★ ⚠ same type
ADCY2 c.2094+16C>T Benign ★★ same type
ADCY2 c.2094+6T>C Benign ★★ same type
ADCY2 p.Cys887= Benign ★★ same type
ADCY2 p.Ser928= Benign ★★ same type
ADCY2 p.Ala634Val Uncertain significance ★ ⚠ same type
ADCY2 p.Ala63Gly Uncertain significance ★ ⚠ same type
ADCY2 p.Ala694Asp 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/adcy2-p-cys654arg (accessed [today's date]).

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