Is ADCY10 p.Ser998Pro (c.2992T>C) pathogenic?

ADCY10 p.Ser998Pro (c.2992T>C) is classified Uncertain significance in ADCY10 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0978); Very rare (popmax 0.0011%, sas).

How common is ADCY10 p.Ser998Pro (c.2992T>C) in the general population?

ADCY10 p.Ser998Pro (c.2992T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ADCY10 p.Ser998Pro (c.2992T>C)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

ADCY10 p.Ser998Pro

c.2992T>C · rs1292789144 · VCV3081225

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -3.2
Regional constraint	o/e 0.90	unconstrained · MANE · 95 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	5.493	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.84e-05% 1/1,461,854 alleles · very rare

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: ADCY10
Protein: p.Ser998Pro
Coding: c.2992T>C
MANE Select: NM_018417
dbSNP: rs1292789144
Type: single nucleotide variant
Location: chr1:167845578 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 37 PDB

Full ADCY10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADCY10 c.1139+6T>G Uncertain significance ★★ same type
ADCY10 c.253+4A>G Uncertain significance ★★ same type
ADCY10 p.Ala103Ser Uncertain significance ★★ ⚠ same type
ADCY10 p.Ala1278Asp Uncertain significance ★★ ⚠ same type
ADCY10 p.Ala862Gly Uncertain significance ★★ ⚠ same type
ADCY10 p.Ala991Ser Uncertain significance ★★ ⚠ same type
ADCY10 p.Arg1207Trp Uncertain significance ★★ ⚠ same type
ADCY10 p.Arg1217His 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/adcy10-p-ser998pro (accessed [today's date]).

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