# NM_003212.4(CRIPTO):c.35+279G>A

https://sugi.bio/variant/cripto-c-35-plus-279g-a

## Summary

**CRIPTO c.35+279G>A** is classified **Likely benign** in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-29). Common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Likely benign · review: Single submitter · rsID rs56197743 · 1 submitter · common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CRIPTO 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 | [CRIPTO](https://sugi.bio/atlas/gene/CRIPTO/) |
| Coding change (HGVS c.) | c.35+279G>A |
| MANE Select transcript | [NM_003212](https://www.ncbi.nlm.nih.gov/nuccore/NM_003212) |
| dbSNP | [rs56197743](https://www.ncbi.nlm.nih.gov/snp/rs56197743/) |
| Variant type | single nucleotide variant |
| Location | chr3:46578283-46578283 (GRCh38) |
| ClinVar | [VCV1317567](https://www.ncbi.nlm.nih.gov/clinvar/variation/1317567/) |

**All HGVS expressions:** `NC_000003.11:g.46619773G>A`, `NC_000003.12:g.46578283G>A`, `NG_017049.1:g.8729G>A`, `NG_021214.1:g.6800C>T`, `NM_001174136.2:c.-13-812G>A`, `NM_003212.4:c.35+279G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 16%, eas) — 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 -1.776, GERP -2.44 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.065**. 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.*
- Splice region: **deep intronic (+279 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 0.99**, o/e 0.92 (1 kb window 46,578,000–46,579,000). 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **16%** (eas) · FAF95 15% · FAF99 14.7% · 809/5,072 in the highest group · 5,339/149,466 alleles overall — common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 16% | 6 |
| South Asian | 15.2% | 7 |
| Middle Eastern | 9.03% | 11 |
| Amish (not grpmax-eligible) | 7.14% | 14 |
| Admixed American | 5.27% | 19 |
| Remaining individuals (not grpmax-eligible) | 4.22% | 24 |
| Finnish (not grpmax-eligible) | 4.1% | 24 |
| Ashkenazi Jewish (not grpmax-eligible) | 3.41% | 29 |
| European (non-Finnish) | 2.83% | 35 |
| African / African-American | 1% | 100 |

*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, 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):

- **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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-09-29 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## 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 2026-10-11); 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 1317567). 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.*