Is CRIPT p.Ala45fs (c.133_134insGG) pathogenic?

CRIPT p.Ala45fs (c.133134insGG) is classified Pathogenic in CRIPT (ClinVar, No assertion criteria, 2 submitters; last evaluated 2014-02-01). Absent from gnomAD; Associated with Rothmund-Thomson syndrome type 3.

What condition is associated with CRIPT p.Ala45fs (c.133_134insGG)?

CRIPT p.Ala45fs (c.133_134insGG) is associated with Rothmund-Thomson syndrome type 3, isolated growth hormone deficiency type IA (ClinVar).

How common is CRIPT p.Ala45fs (c.133_134insGG) in the general population?

CRIPT p.Ala45fs (c.133_134insGG) is absent from gnomAD (gnomAD).

How is Rothmund-Thomson syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CRIPT p.Ala45fs

c.133_134insGG · rs587779356 · VCV127249

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Rothmund-Thomson syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.45, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CRIPT
Protein: p.Ala45fs
Coding: c.133_134insGG
MANE Select: NM_014171
dbSNP: rs587779356
Type: Insertion
Location: chr2:46619676 (GRCh38)
Gene constraint: LOEUF 1.852 · pLI 0.19 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.77 · 1 PDB

Full CRIPT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rothmund-Thomson syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated growth hormone deficiency type IA

For Rothmund-Thomson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CRIPT p.Ala45Pro Uncertain significance ★★ ⚠ same residue
CRIPT p.Ala45Thr Uncertain significance ★ ⚠ same residue
CRIPT p.Ala45= Likely benign ★ same residue
CRIPT p.Ser64Phe Uncertain significance ★★ ⚠ same condition
CRIPT c.-422_17-582del Pathogenic ★ same condition
CRIPT p.Cys3fs Pathogenic ★ same condition
CRIPT p.Cys3Tyr Likely pathogenic ★ same condition
CRIPT p.Cys58Ter Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cript-p-ala45fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown