# NM_003816.3(ADAM9):c.96A>G (p.Pro32=)

https://sugi.bio/variant/adam9-p-pro32

## Summary

**ADAM9 p.Pro32= (c.96A>G)** is classified **Uncertain significance** in ADAM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). Very rare (popmax 0.0067%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs772194829 · 1 submitter · very rare (popmax 0.0067%, amr)

## For patients & families {#patients}

This is a change in the ADAM9 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADAM9](https://sugi.bio/atlas/gene/ADAM9/) |
| Protein change (HGVS p.) | p.Pro32= |
| Coding change (HGVS c.) | c.96A>G |
| MANE Select transcript | [NM_003816](https://www.ncbi.nlm.nih.gov/nuccore/NM_003816) |
| dbSNP | [rs772194829](https://www.ncbi.nlm.nih.gov/snp/rs772194829/) |
| Variant type | single nucleotide variant |
| Location | chr8:38997159-38997159 (GRCh38) |
| ClinVar | [VCV1044936](https://www.ncbi.nlm.nih.gov/clinvar/variation/1044936/) |

**All HGVS expressions:** `NC_000008.10:g.38854678A>G`, `NC_000008.11:g.38997159A>G`, `NG_016335.1:g.5174A>G`, `NM_003816.3:c.96A>G`, `NR_027638.2:n.187A>G`, `NR_027639.2:n.187A>G`, `NR_027878.2:n.187A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.791, GERP 0.669, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 23.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.15**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.15**, acceptor gain **0.00**, donor gain **0.29**.
- Pangolin: Δ**0.36** (loss), gain 0.15 / loss 0.36. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0067%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/59,690 in the highest group · 6/1,445,654 alleles overall — very rare (popmax 0.0067%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0067% | 14,922 |
| European (non-Finnish) | 0.00017% | 589,175 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ADAM9** population constraint: LOEUF 0.575, pLI 0.0018051, missense-Z 2.3253; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ADAM9-related retinopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.14, 40% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ADAM9 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ADAM9's established molecular role includes metalloendopeptidase activity.


### Pathways affected {#pathways}

ADAM9 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** metalloendopeptidase activity, integrin binding, collagen binding, metallopeptidase activity, SH3 domain binding, laminin binding.

**Biological process:** membrane protein ectodomain proteolysis, cell adhesion, cell-matrix adhesion, transforming growth factor beta receptor signaling pathway, response to manganese ion, protein processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-03 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related ADAM9 variant pages (same residue, condition, or type): [ADAM9 p.Tyr213Ter](/variant/adam9-p-tyr213ter), [ADAM9 c.195+5G>A](/variant/adam9-c-195-plus-5g-a), [ADAM9 c.997-3C>G](/variant/adam9-c-997-minus-3c-g), [ADAM9 p.Ala145Glu](/variant/adam9-p-ala145glu), [ADAM9 p.Ala424Thr](/variant/adam9-p-ala424thr), [ADAM9 p.Ala510Thr](/variant/adam9-p-ala510thr), [ADAM9 p.Ala534Pro](/variant/adam9-p-ala534pro), [ADAM9 p.Arg117Trp](/variant/adam9-p-arg117trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1044936). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*