Is ADCY2 p.Leu46Phe (c.136C>T) pathogenic?

ADCY2 p.Leu46Phe (c.136C>T) is classified Uncertain significance in ADCY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9); Very rare (popmax 0.00177%, amr).

How common is ADCY2 p.Leu46Phe (c.136C>T) in the general population?

ADCY2 p.Leu46Phe (c.136C>T) is very rare (popmax 0.00177%, amr) (gnomAD).

What do computational predictors say about ADCY2 p.Leu46Phe (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.9) — an in-silico prediction, not a clinical call.

ADCY2 p.Leu46Phe

c.136C>T · rs2477788812 · VCV2298935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9	likely pathogenic
REVEL	0.38	indeterminate
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 18 kb · p 0.63 · regional, not allelic
Overall
CADD	23.8	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 0.00177% Admixed American · 1/56,548 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00021% 3/1,428,752 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00177%	56,548
European (non-Finnish)	0.000172%	581,852

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.Leu46Phe
Coding: c.136C>T
MANE Select: NM_020546
dbSNP: rs2477788812
Type: single nucleotide variant
Location: chr5:7396432 (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-leu46phe (accessed [today's date]).

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