# NM_003212.4(CRIPTO):c.45G>T (p.Trp15Cys)

https://sugi.bio/variant/cripto-p-trp15cys

## Summary

**CRIPTO p.Trp15Cys (c.45G>T)** is classified **Uncertain significance** in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1779); Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1311886156 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the CRIPTO 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 | [CRIPTO](https://sugi.bio/atlas/gene/CRIPTO/) |
| Protein change (HGVS p.) | p.Trp15Cys |
| Coding change (HGVS c.) | c.45G>T |
| MANE Select transcript | [NM_003212](https://www.ncbi.nlm.nih.gov/nuccore/NM_003212) |
| dbSNP | [rs1311886156](https://www.ncbi.nlm.nih.gov/snp/rs1311886156/) |
| Variant type | single nucleotide variant |
| Location | chr3:46579104-46579104 (GRCh38) |
| ClinVar | [VCV3235395](https://www.ncbi.nlm.nih.gov/clinvar/variation/3235395/) |

**All HGVS expressions:** `NC_000003.11:g.46620594G>T`, `NC_000003.12:g.46579104G>T`, `NG_017049.1:g.9550G>T`, `NG_021214.1:g.5979C>A`, `NG_099261.1:g.566G>T`, `NG_099261.2:g.566G>T`, `NM_001174136.2:c.-4G>T`, `NM_003212.4:c.45G>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** (0.1779)
- REVEL 0.086 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.905 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.762, GERP -3.69, phastCons 0.979 — weakly conserved position
- CADD: **PHRED 18.41**. 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 0.91** across the covering region of the MANE Select transcript (46,577,970–46,581,247), spanning 3,277 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.45**, donor loss **0.35**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 9 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.37** (loss), gain 0.00 / loss 0.37. 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,028 in the highest group · 3/1,614,116 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,502 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,012 |

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-03.

**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 | 2024-01-03 |

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

## Similar variants {#similar}

Related CRIPTO variant pages (same residue, condition, or type): [CRIPTO c.339-8A>G](/variant/cripto-c-339-minus-8a-g), [CRIPTO p.Arg111Gly](/variant/cripto-p-arg111gly), [CRIPTO p.Gly151=](/variant/cripto-p-gly151), [CRIPTO p.Arg111His](/variant/cripto-p-arg111his), [CRIPTO p.Arg171His](/variant/cripto-p-arg171his), [CRIPTO p.Arg38Cys](/variant/cripto-p-arg38cys), [CRIPTO p.Arg38His](/variant/cripto-p-arg38his), [CRIPTO p.Arg60Gln](/variant/cripto-p-arg60gln).

### 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 3235395). 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.*