Is ADCY2 p.Phe140Ser (c.419T>C) pathogenic?

ADCY2 p.Phe140Ser (c.419T>C) is classified Uncertain significance in ADCY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9127); Absent from gnomAD v4.1.

How common is ADCY2 p.Phe140Ser (c.419T>C) in the general population?

ADCY2 p.Phe140Ser (c.419T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADCY2 p.Phe140Ser (c.419T>C)?

AlphaMissense predicts likely pathogenic (score 0.9127) — an in-silico prediction, not a clinical call.

ADCY2 p.Phe140Ser

c.419T>C · VCV4235236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9127 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9127	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 212 kb · p 0.0014 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADCY2
Protein: p.Phe140Ser
Coding: c.419T>C
MANE Select: NM_020546
Type: single nucleotide variant
Location: chr5:7520748 (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-phe140ser (accessed [today's date]).

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