# NM_003212.4(CRIPTO):c.*277del

https://sugi.bio/variant/cripto-c-star-277del

## Summary

**CRIPTO c.*277del** is classified **Benign** in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-02). Common (popmax 29.4%, mid) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs57921531 · 1 submitter · common (popmax 29.4%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CRIPTO gene that is classified as 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 | [CRIPTO](https://sugi.bio/atlas/gene/CRIPTO/) |
| Coding change (HGVS c.) | c.*277del |
| MANE Select transcript | [NM_003212](https://www.ncbi.nlm.nih.gov/nuccore/NM_003212) |
| dbSNP | [rs57921531](https://www.ncbi.nlm.nih.gov/snp/rs57921531/) |
| Variant type | Deletion |
| Location | chr3:46581511-46581511 (GRCh38) |
| ClinVar | [VCV1228755](https://www.ncbi.nlm.nih.gov/clinvar/variation/1228755/) |

**All HGVS expressions:** `NC_000003.11:g.46623017del`, `NC_000003.12:g.46581527del`, `NG_017049.1:g.11973del`, `NG_021214.1:g.3572del`, `NM_001174136.2:c.*277del`, `NM_003212.4:c.*277del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 29.4%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 0.141, GERP 0.382, phastCons 0.003 — weakly conserved position
- CADD: **PHRED 1.117**. 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.*
- Non-coding constraint (Gnocchi): **Z 0.70**, o/e 0.95 (1 kb window 46,581,000–46,582,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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.
- Repeat context: **sine, segmental_duplication** (AluSx3, chr19:39534904, chr2:227869169). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **29.4%** (mid) · FAF95 28% · FAF99 27.9% · 580/1,970 in the highest group · 138,430/519,910 alleles overall — common (popmax 29.4%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 30.1% | 3 |
| Middle Eastern (grpmax) | 29.4% | 3 |
| European (non-Finnish) | 28.1% | 4 |
| South Asian | 28.1% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 27% | 4 |
| East Asian | 25.6% | 4 |
| Finnish (not grpmax-eligible) | 24.4% | 4 |
| Admixed American | 22.9% | 4 |
| African / African-American | 18.5% | 5 |
| Amish (not grpmax-eligible) | 16.6% | 6 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CRIPTO** population constraint: ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **congenital heart disease** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.47, 31% of residues very-high.

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

*Describes the biological roles of CRIPTO (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:** CRIPTO's established molecular role includes signaling receptor binding.


### Pathways affected {#pathways}

CRIPTO participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation](https://reactome.org/content/detail/R-HSA-2892247) | curated |
| [Regulation of signaling by NODAL](https://reactome.org/content/detail/R-HSA-1433617) | electronic |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | electronic |

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

**Molecular function:** signaling receptor binding, growth factor activity.

**Biological process:** cell migration involved in sprouting angiogenesis, heart development, positive regulation of cell population proliferation, regulation of signal transduction, positive regulation of endothelial cell migration, positive regulation of cell migration.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-02.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-09-02 |

**Reported phenotype names (ClinVar):** not provided, none provided.

### 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 1228755). 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.*