# NM_014171.6(CRIPT):c.133_134insGG (p.Ala45fs)

https://sugi.bio/variant/cript-p-ala45fs

## Summary

**CRIPT p.Ala45fs (c.133_134insGG)** is classified **Pathogenic** in CRIPT (ClinVar, No assertion criteria, 2 submitters; last evaluated 2014-02-01). No gnomAD frequency available for this variant; Associated with Rothmund-Thomson syndrome type 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs587779356 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CRIPT gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Rothmund-Thomson syndrome type 3.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CRIPT is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Rothmund-Thomson syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Skin rash — Very frequent (99-80%)
- Poikiloderma — Very frequent (99-80%)
- Malar rash — Very frequent (99-80%)
- Abnormality of the dentition — Frequent (79-30%)
- Sparse eyelashes — Frequent (79-30%)
- Infertility — Frequent (79-30%)
- Abnormality of the skeletal system — Frequent (79-30%)
- Small for gestational age — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027860/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRIPT](https://sugi.bio/atlas/gene/CRIPT/) |
| Protein change (HGVS p.) | p.Ala45fs |
| Coding change (HGVS c.) | c.133_134insGG |
| MANE Select transcript | [NM_014171](https://www.ncbi.nlm.nih.gov/nuccore/NM_014171) |
| dbSNP | [rs587779356](https://www.ncbi.nlm.nih.gov/snp/rs587779356/) |
| Variant type | Insertion |
| Location | chr2:46619676-46619677 (GRCh38) |
| ClinVar | [VCV127249](https://www.ncbi.nlm.nih.gov/clinvar/variation/127249/) |

**All HGVS expressions:** `NC_000002.11:g.46846816_46846817insGG`, `NC_000002.12:g.46619677_46619678insGG`, `NG_034144.1:g.7506_7507insGG`, `NM_014171.6:c.133_134insGG`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.115, GERP 0.451, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.852, pLI 0.18985. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 5**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CRIPT** population constraint: LOEUF 1.852, pLI 0.18985, missense-Z -0.57206; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.77, 36% of residues very-high.

**1 experimental structure(s)** (PDB): [7DVQ](https://www.rcsb.org/structure/7DVQ).

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

*Describes the biological roles of CRIPT (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:** CRIPT's established molecular role includes PDZ domain binding.


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

**Molecular function:** PDZ domain binding, scaffold protein binding.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2014-02-01.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2014); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | no assertion criteria provided | research |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-02-01 |

## Associated conditions {#conditions}

[Rothmund-Thomson syndrome type 3](https://sugi.bio/atlas/disease/rothmund-thomson-syndrome-type-3/), [isolated growth hormone deficiency type IA](https://sugi.bio/atlas/disease/isolated-growth-hormone-deficiency-type-ia/).

**Reported phenotype names (ClinVar):** Rothmund-Thomson syndrome type 3, Ateleiotic dwarfism, Short stature with microcephaly and distinctive facies, Isolated growth hormone deficiency type 1A, Growth hormone deficiency, isolated autosomal recessive, ILLIG type growth hormone deficiency, Pituitary dwarfism 1, IGHD IA, PITUITARY DWARFISM I, SEXUAL ATELEIOTIC DWARFISM.

## Similar variants {#similar}

Related CRIPT variant pages (same residue, condition, or type): [CRIPT p.Ala45Pro](/variant/cript-p-ala45pro), [CRIPT p.Ala45Thr](/variant/cript-p-ala45thr), [CRIPT p.Ala45=](/variant/cript-p-ala45), [CRIPT p.Ser64Phe](/variant/cript-p-ser64phe), [CRIPT c.-422_17-582del](/variant/cript-c-minus-422-17-minus-582del), [CRIPT p.Cys3fs](/variant/cript-p-cys3fs), [CRIPT p.Cys3Tyr](/variant/cript-p-cys3tyr), [CRIPT p.Cys58Ter](/variant/cript-p-cys58ter).

### 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 127249). 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.*