Is ADCY2 p.Ala862Val (c.2585C>T) pathogenic?

ADCY2 p.Ala862Val (c.2585C>T) is classified Uncertain significance in ADCY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely benign (0.208); Very rare (popmax 0.00837%, amr).

How common is ADCY2 p.Ala862Val (c.2585C>T) in the general population?

ADCY2 p.Ala862Val (c.2585C>T) is very rare (popmax 0.00837%, amr) (gnomAD).

What do computational predictors say about ADCY2 p.Ala862Val (c.2585C>T)?

AlphaMissense predicts likely benign (score 0.208) — an in-silico prediction, not a clinical call.

ADCY2 p.Ala862Val

c.2585C>T · VCV3833173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00837%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.208	likely benign
REVEL	0.621	indeterminate
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 54 kb · p 9.7e-25 · regional, not allelic
Overall
CADD	27.1	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 0.00837% Admixed American · 5/59,758 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00354% 57/1,611,050 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00837%	11,952
African / African-American	0.00538%	18,583
European (non-Finnish)	0.00382%	26,207
East Asian	0.00224%	44,700
Remaining individualsnot grpmax-eligible	0.0016%	62,384
South Asian	0.0011%	90,782

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.Ala862Val
Coding: c.2585C>T
MANE Select: NM_020546
Type: single nucleotide variant
Location: chr5:7789757 (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-ala862val (accessed [today's date]).

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