# NM_001856.4(COL16A1):c.2177C>T (p.Ala726Val)

https://sugi.bio/variant/col16a1-p-ala726val

## Summary

**COL16A1 p.Ala726Val (c.2177C>T)** is classified **Uncertain significance** in COL16A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.000178%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000178%, nfe)

## For patients & families {#patients}

This is a change in the COL16A1 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 | [COL16A1](https://sugi.bio/atlas/gene/COL16A1/) |
| Protein change (HGVS p.) | p.Ala726Val |
| Coding change (HGVS c.) | c.2177C>T |
| MANE Select transcript | [NM_001856](https://www.ncbi.nlm.nih.gov/nuccore/NM_001856) |
| Variant type | single nucleotide variant |
| Location | chr1:31684215-31684215 (GRCh38) |
| ClinVar | [VCV3495154](https://www.ncbi.nlm.nih.gov/clinvar/variation/3495154/) |

**All HGVS expressions:** `NC_000001.10:g.32149816G>A`, `NC_000001.11:g.31684215G>A`, `NM_001856.4:c.2177C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0917)
- REVEL 0.47 (indeterminate)
- SaProt LLR -6.34 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.905, GERP 2.18, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (31,661,456–31,702,193), spanning 40,737 bp. Chi-square p 0.035. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- Pangolin: Δ**0.38** (gain), gain 0.38 / loss 0.21. Agrees with SpliceAI. 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 **0.000178%** (nfe) · FAF95 3e-05% · FAF99 1.1e-05% · 2/1,126,234 in the highest group · 2/1,509,364 alleles overall — very rare (popmax 0.000178%, nfe).

*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}

**COL16A1** population constraint: LOEUF 0.794, pLI 4.272e-41, missense-Z 1.7469; ClinGen dosage — haploinsufficiency dosage-sensitivity unlikely, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **726** lies in the 'disordered' region; the 'nonhelical region 6 (nc6)' region.

AlphaFold model confidence (whole protein): pLDDT 49.60, 11% of residues very-high.

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

*Describes the biological roles of COL16A1 (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:** COL16A1's established molecular role includes integrin binding. p.Ala726Val falls in the disordered region.


### Pathways affected {#pathways}

COL16A1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [Collagen chain trimerization](https://reactome.org/content/detail/R-HSA-8948216) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |

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

**Molecular function:** integrin binding, extracellular matrix structural constituent conferring tensile strength.

**Biological process:** cell adhesion, integrin activation, cell adhesion mediated by integrin, positive regulation of focal adhesion assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related COL16A1 variant pages (same residue, condition, or type): [COL16A1 c.1258-5C>G](/variant/col16a1-c-1258-minus-5c-g), [COL16A1 c.982-10G>A](/variant/col16a1-c-982-minus-10g-a), [COL16A1 p.Lys398Arg](/variant/col16a1-p-lys398arg), [COL16A1 p.Pro903Gln](/variant/col16a1-p-pro903gln), [COL16A1 p.Thr62Lys](/variant/col16a1-p-thr62lys), [COL16A1 p.Ala1005Gly](/variant/col16a1-p-ala1005gly), [COL16A1 p.Ala1212Thr](/variant/col16a1-p-ala1212thr), [COL16A1 p.Ala1385Val](/variant/col16a1-p-ala1385val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3495154). 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.*