Is ADAM21 p.Pro485Ser (c.1453C>T) pathogenic?

ADAM21 p.Pro485Ser (c.1453C>T) is classified Uncertain significance in ADAM21 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.2733); Very rare (popmax 0.00667%, amr).

How common is ADAM21 p.Pro485Ser (c.1453C>T) in the general population?

ADAM21 p.Pro485Ser (c.1453C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ADAM21 p.Pro485Ser (c.1453C>T)?

AlphaMissense predicts likely benign (score 0.2733) — an in-silico prediction, not a clinical call.

ADAM21 p.Pro485Ser

c.1453C>T · rs747032678 · VCV2345699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2733	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	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	24.5	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 0.00667% Admixed American · 4/59,988 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00291% 47/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
European (non-Finnish)	0.00356%	28,096
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro485Ser
Coding: c.1453C>T
MANE Select: NM_003813
dbSNP: rs747032678
Type: single nucleotide variant
Location: chr14:70458952 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 83.17
Residue 485: the disintegrin domain

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

Similar variants

ADAM21 p.Pro485Ala Uncertain significance ★ ⚠ same residue
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

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-pro485ser (accessed [today's date]).

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