Is ADAMDEC1 p.Leu321Pro (c.962T>C) pathogenic?

ADAMDEC1 p.Leu321Pro (c.962T>C) is classified Uncertain significance in ADAMDEC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.8405); Very rare (popmax 6.84e-05%).

How common is ADAMDEC1 p.Leu321Pro (c.962T>C) in the general population?

ADAMDEC1 p.Leu321Pro (c.962T>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ADAMDEC1 p.Leu321Pro (c.962T>C)?

AlphaMissense predicts likely pathogenic (score 0.8405) — an in-silico prediction, not a clinical call.

ADAMDEC1 p.Leu321Pro

c.962T>C · rs753778596 · VCV3146434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8405	likely pathogenic
REVEL	0.389	indeterminate
SaProt	LLR -16.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.5	GERP 0.87, phastCons 0.97
Regional constraint	o/e 1.05	unconstrained · MANE · 21 kb · p 0.21 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,730 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: ADAMDEC1
Protein: p.Leu321Pro
Coding: c.962T>C
dbSNP: rs753778596
Type: single nucleotide variant
Location: chr8:24399425 (GRCh38)

Full ADAMDEC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/adamdec1-p-leu321pro (accessed [today's date]).

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