Is ADAM30 p.Pro566Ser (c.1696C>T) pathogenic?

ADAM30 p.Pro566Ser (c.1696C>T) is classified Uncertain significance in ADAM30 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: ambiguous (0.5124); Ultra-rare (popmax 0.0198%, sas).

How common is ADAM30 p.Pro566Ser (c.1696C>T) in the general population?

ADAM30 p.Pro566Ser (c.1696C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about ADAM30 p.Pro566Ser (c.1696C>T)?

AlphaMissense predicts ambiguous (score 0.5124) — an in-silico prediction, not a clinical call.

ADAM30 p.Pro566Ser

c.1696C>T · VCV3487881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5124	ambiguous
REVEL	0.178	moderately benign-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,369 bp · p 0.98 · regional, not allelic
Overall
CADD	23.1	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 0.0198% South Asian · 18/91,084 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00112% 18/1,613,934 alleles · ultra-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: ADAM30
Protein: p.Pro566Ser
Coding: c.1696C>T
MANE Select: NM_021794
Type: single nucleotide variant
Location: chr1:119894641 (GRCh38)
Gene constraint: LOEUF 1.903 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 79.68

Full ADAM30 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM30 p.Ala124Ser Uncertain significance ★ ⚠ same type
ADAM30 p.Ala230Thr Uncertain significance ★ ⚠ same type
ADAM30 p.Ala518Pro Uncertain significance ★ ⚠ same type
ADAM30 p.Ala550Thr Uncertain significance ★ ⚠ same type
ADAM30 p.Arg215Gly Uncertain significance ★ ⚠ same type
ADAM30 p.Arg245His Uncertain significance ★ ⚠ same type
ADAM30 p.Arg275Thr Uncertain significance ★ ⚠ same type
ADAM30 p.Arg287His 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/adam30-p-pro566ser (accessed [today's date]).

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