Is ADAM8 p.Arg73Gln (c.218G>A) pathogenic?

ADAM8 p.Arg73Gln (c.218G>A) is classified Uncertain significance in ADAM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0672); Very rare (popmax 0.00865%, amr).

How common is ADAM8 p.Arg73Gln (c.218G>A) in the general population?

ADAM8 p.Arg73Gln (c.218G>A) is very rare (popmax 0.00865%, amr) (gnomAD).

What do computational predictors say about ADAM8 p.Arg73Gln (c.218G>A)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

ADAM8 p.Arg73Gln

c.218G>A · VCV4637464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00865%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -1.3, phastCons 0.004
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.43 · regional, not allelic
Overall
CADD	18.18	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 0.00865% Admixed American · 5/57,780 alleles

Filtering AF 0.00398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00365%

Overall 0.00447% 71/1,587,594 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00865%	11,556
European (non-Finnish)	0.00506%	19,769
East Asian	0.00449%	22,280
Ashkenazi Jewishnot grpmax-eligible	0.0036%	27,770
African / African-American	0.00269%	37,186
Remaining individualsnot grpmax-eligible	0.00163%	61,260
South Asian	0.00114%	87,560

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: ADAM8
Protein: p.Arg73Gln
Coding: c.218G>A
MANE Select: NM_001109
Type: single nucleotide variant
Location: chr10:133274168 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.28 · 1 PDB

Full ADAM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM8 p.Ala118= Benign ★★ same type
ADAM8 p.Ala490Thr Benign ★★ same type
ADAM8 p.Arg36His Benign ★★ ⚠ same type
ADAM8 p.Arg433Cys Benign ★★ ⚠ same type
ADAM8 c.228-2A>G Uncertain significance ★ same type
ADAM8 p.Ala119Ser Uncertain significance ★ ⚠ same type
ADAM8 p.Ala119Thr Uncertain significance ★ ⚠ same type
ADAM8 p.Ala164Ser 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/adam8-p-arg73gln (accessed [today's date]).

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