Is ADAM21 p.Ile571Phe (c.1711A>T) pathogenic?

ADAM21 p.Ile571Phe (c.1711A>T) is classified Uncertain significance in ADAM21 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0873); Ultra-rare (popmax 0.0133%, amr).

How common is ADAM21 p.Ile571Phe (c.1711A>T) in the general population?

ADAM21 p.Ile571Phe (c.1711A>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about ADAM21 p.Ile571Phe (c.1711A>T)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

ADAM21 p.Ile571Phe

c.1711A>T · rs747464512 · VCV2359431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -3.49	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 1	GERP -0.58, phastCons 0.028
Regional constraint	o/e 0.73	unconstrained · MANE · 1,511 bp · p 4.1e-11 · regional, not allelic
Overall
CADD	18.89	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 0.0133% Admixed American · 8/59,990 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000867% 14/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000424%	236,004

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.Ile571Phe
Coding: c.1711A>T
MANE Select: NM_003813
dbSNP: rs747464512
Type: single nucleotide variant
Location: chr14:70459210 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 83.17

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-ile571phe (accessed [today's date]).

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