# NM_003816.3(ADAM9):c.774G>A (p.Val258=)

https://sugi.bio/variant/adam9-p-val258

## Summary

**ADAM9 p.Val258= (c.774G>A)** is classified **Likely benign** in ADAM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). Very rare (popmax 0.00167%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ADAM9 gene that is classified as likely benign — not considered disease-causing, 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.Val258= |
| Coding change (HGVS c.) | c.774G>A |
| MANE Select transcript | [NM_003816](https://www.ncbi.nlm.nih.gov/nuccore/NM_003816) |
| Variant type | single nucleotide variant |
| Location | chr8:39023185-39023185 (GRCh38) |
| ClinVar | [VCV4770768](https://www.ncbi.nlm.nih.gov/clinvar/variation/4770768/) |

**All HGVS expressions:** `NC_000008.10:g.38880704G>A`, `NC_000008.11:g.39023185G>A`, `NG_016335.1:g.31200G>A`, `NG_016335.2:g.31214G>A`, `NM_003816.3:c.774G>A`, `NR_027638.2:n.865G>A`, `NR_027639.2:n.865G>A`, `NR_027878.2:n.865G>A`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.084, GERP -3.66, phastCons 0.629 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.405**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.78 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,970 in the highest group · 2/1,461,336 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,970 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,472 |

*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}

Residue **258** lies in the peptidase m12b domain.

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. p.Val258= falls in the peptidase m12b domain.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-19 |

**Reported phenotype names (ClinVar):** not provided, 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 4770768). 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.*