Is ADCY3 p.Phe231= (c.693C>T) pathogenic?

ADCY3 p.Phe231= (c.693C>T) is classified Likely benign in ADCY3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-08-17). Ultra-rare (popmax 0.0121%, sas); Associated with ADCY3-related disorder.

What condition is associated with ADCY3 p.Phe231= (c.693C>T)?

ADCY3 p.Phe231= (c.693C>T) is associated with ADCY3-related disorder (ClinVar).

How common is ADCY3 p.Phe231= (c.693C>T) in the general population?

ADCY3 p.Phe231= (c.693C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

ADCY3 p.Phe231=

c.693C>T · VCV3351555

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Conditions

ADCY3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -2.1, phastCons 1
Overall
CADD	10.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,074 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00124% 20/1,613,932 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000678%	147,493

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.Phe231=
Coding: c.693C>T
MANE Select: NM_004036
Type: single nucleotide variant
Location: chr2:24872702 (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

ADCY3-related disorder

Similar variants

ADCY3 p.Val195Met Uncertain significance ★★ ⚠ same condition
ADCY3 c.2496-13C>T Uncertain significance ★ same condition
ADCY3 p.Arg252Cys Uncertain significance ★ ⚠ same condition
ADCY3 p.Arg564His Uncertain significance ★ ⚠ same condition
ADCY3 p.Arg623Cys Uncertain significance ★ ⚠ same condition
ADCY3 p.Glu346Lys Uncertain significance ★ ⚠ same condition
ADCY3 p.Met461Ile Uncertain significance ★ ⚠ same condition
ADCY3 p.Thr738Met 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-phe231 (accessed [today's date]).

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