Is ADCY7 p.Pro519Ser (c.1555C>T) pathogenic?

ADCY7 p.Pro519Ser (c.1555C>T) is classified Uncertain significance in ADCY7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.0851); Ultra-rare (popmax 0.0175%, mid).

How common is ADCY7 p.Pro519Ser (c.1555C>T) in the general population?

ADCY7 p.Pro519Ser (c.1555C>T) is ultra-rare (popmax 0.0175%, mid) (gnomAD).

What do computational predictors say about ADCY7 p.Pro519Ser (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

ADCY7 p.Pro519Ser

c.1555C>T · VCV4012491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.5	GERP -3.3, phastCons 0.5
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 6.6e-09 · regional, not allelic
Overall
CADD	12.84	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 0.0175% Middle Eastern · 1/5,706 alleles

Filtering AF 0.000301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000844% 13/1,540,858 alleles · ultra-rare exomes 12/1,388,670 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0175%	5,706
Remaining individualsnot grpmax-eligible	0.00507%	19,710
South Asian	0.00124%	80,840
European (non-Finnish)	0.000701%	142,709

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: ADCY7
Protein: p.Pro519Ser
Coding: c.1555C>T
MANE Select: NM_001114
Type: single nucleotide variant
Location: chr16:50304546 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.32
Residue 519: the 'disordered' region; the 'modulates adenylate cyclase activity by modulating the binding of g(s)alpha to the high-affinity g(s)alpha binding site in 7c1a/7c2' region

Full ADCY7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADCY7 p.Arg1051= Benign ★★ same type
ADCY7 p.Gly555= Benign ★★ same type
ADCY7 p.His343= Benign ★★ same type
ADCY7 p.Ile933= Likely benign ★★ same type
ADCY7 p.Ser944= Benign ★★ same type
ADCY7 p.Ala195Val Uncertain significance ★ ⚠ same type
ADCY7 p.Ala204Val Uncertain significance ★ ⚠ same type
ADCY7 p.Ala344Val 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/adcy7-p-pro519ser (accessed [today's date]).

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