# NM_015692.5(CPAMD8):c.2141del (p.Asp714fs)

https://sugi.bio/variant/cpamd8-p-asp714fs

## Summary

**CPAMD8 p.Asp714fs (c.2141del)** is classified **Likely pathogenic** in CPAMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). Associated with anterior segment dysgenesis 8.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CPAMD8 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to anterior segment dysgenesis 8.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017954/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPAMD8](https://sugi.bio/atlas/gene/CPAMD8/) |
| Protein change (HGVS p.) | p.Asp714fs |
| Coding change (HGVS c.) | c.2141del |
| MANE Select transcript | [NM_015692](https://www.ncbi.nlm.nih.gov/nuccore/NM_015692) |
| Variant type | Deletion |
| Location | chr19:16970963-16970963 (GRCh38) |
| ClinVar | [VCV4849467](https://www.ncbi.nlm.nih.gov/clinvar/variation/4849467/) |

**All HGVS expressions:** `NC_000019.10:g.16970963del`, `NC_000019.9:g.17081773del`, `NG_054892.1:g.60856del`, `NM_015692.5:c.2141del`, `NR_165644.1:n.1677del`

## 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 -6.793, GERP -2.35 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.825, pLI 4.7182e-30. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 42**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**CPAMD8** population constraint: LOEUF 0.825, pLI 4.7182e-30, missense-Z 0.68676. *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):

- **anterior segment dysgenesis 8** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.99, 18% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-23 |

## Associated conditions {#conditions}

[anterior segment dysgenesis 8](https://sugi.bio/atlas/disease/anterior-segment-dysgenesis-8/).

**Reported phenotype names (ClinVar):** Anterior segment dysgenesis 8.

## Similar variants {#similar}

Related CPAMD8 variant pages (same residue, condition, or type): [CPAMD8 c.1758+1_1758+4del](/variant/cpamd8-c-1758-plus-1-1758-plus-4del), [CPAMD8 p.Gln1466fs](/variant/cpamd8-p-gln1466fs), [CPAMD8 p.Ser552fs](/variant/cpamd8-p-ser552fs), [CPAMD8 c.2070+1G>A](/variant/cpamd8-c-2070-plus-1g-a), [CPAMD8 p.Arg1117Ter](/variant/cpamd8-p-arg1117ter), [CPAMD8 p.Arg738fs](/variant/cpamd8-p-arg738fs), [CPAMD8 p.Trp178Ter](/variant/cpamd8-p-trp178ter), [CPAMD8 p.Asp169Gly](/variant/cpamd8-p-asp169gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4849467). 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.*