# NM_003212.4(CRIPTO):c.65T>C (p.Val22Ala)

https://sugi.bio/variant/cripto-p-val22ala

## Summary

**CRIPTO p.Val22Ala (c.65T>C)** is classified **Benign** in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-27). AlphaMissense: likely benign (0.0529); Common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs11130097 · 1 submitter · AlphaMissense likely benign · common (popmax 59.2%, sas) — 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/) |
| Protein change (HGVS p.) | p.Val22Ala |
| Coding change (HGVS c.) | c.65T>C |
| MANE Select transcript | [NM_003212](https://www.ncbi.nlm.nih.gov/nuccore/NM_003212) |
| dbSNP | [rs11130097](https://www.ncbi.nlm.nih.gov/snp/rs11130097/) |
| Variant type | single nucleotide variant |
| Location | chr3:46579124-46579124 (GRCh38) |
| ClinVar | [VCV1275194](https://www.ncbi.nlm.nih.gov/clinvar/variation/1275194/) |

**All HGVS expressions:** `NC_000003.11:g.46620614T>C`, `NC_000003.12:g.46579124T>C`, `NG_017049.1:g.9570T>C`, `NG_021214.1:g.5959A>G`, `NM_001174136.2:c.17T>C`, `NM_003212.4:c.65T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0529)
- REVEL 0.069 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.084 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.353, GERP -3.36 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.934**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.24 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **59.2%** (sas) · FAF95 58.7% · FAF99 58.6% · 53,883/91,072 in the highest group · 848,123/1,613,650 alleles overall — common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 59.2% | 2 |
| Middle Eastern | 58.9% | 2 |
| European (non-Finnish) | 53.4% | 2 |
| Amish (not grpmax-eligible) | 52.6% | 2 |
| Finnish (not grpmax-eligible) | 51.9% | 2 |
| Remaining individuals (not grpmax-eligible) | 51.4% | 2 |
| African / African-American | 48.6% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 46.1% | 2 |
| Admixed American | 45.2% | 2 |
| East Asian | 40.3% | 2 |

*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}

Residue **22** lies in a UniProt-annotated variant site (in).

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 2018-11-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-11-27 |

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

## Similar variants {#similar}

Related CRIPTO variant pages (same residue, condition, or type): [CRIPTO p.Val22=](/variant/cripto-p-val22), [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).

### 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 1275194). 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.*