Is ADAM21 p.Cys433Ser (c.1298G>C) pathogenic?

ADAM21 p.Cys433Ser (c.1298G>C) is classified Uncertain significance in ADAM21 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.7534); Very rare (popmax 0.00329%, sas).

How common is ADAM21 p.Cys433Ser (c.1298G>C) in the general population?

ADAM21 p.Cys433Ser (c.1298G>C) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ADAM21 p.Cys433Ser (c.1298G>C)?

AlphaMissense predicts likely pathogenic (score 0.7534) — an in-silico prediction, not a clinical call.

ADAM21 p.Cys433Ser

c.1298G>C · VCV4637372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7534	likely pathogenic · top 7% in ADAM21
REVEL	0.389	indeterminate
SaProt	LLR -11.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 1,511 bp · p 4.1e-11 · regional, not allelic
Overall
CADD	24.4	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,876 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: ADAM21
Protein: p.Cys433Ser
Coding: c.1298G>C
MANE Select: NM_003813
Type: single nucleotide variant
Location: chr14:70458797 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 83.17
Residue 433: the disintegrin domain

Full ADAM21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM21 p.Ala432Asp Uncertain significance ★ ⚠ same type
ADAM21 p.Ala432Thr Uncertain significance ★ ⚠ same type
ADAM21 p.Ala500Ser Uncertain significance ★ ⚠ same type
ADAM21 p.Ala718Pro Uncertain significance ★ ⚠ same type
ADAM21 p.Arg182Cys Uncertain significance ★ ⚠ same type
ADAM21 p.Arg317Cys Uncertain significance ★ ⚠ same type
ADAM21 p.Arg408His Uncertain significance ★ ⚠ same type
ADAM21 p.Arg539His 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/adam21-p-cys433ser (accessed [today's date]).

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