Is CRIPT p.Cys76Tyr (c.227G>A) pathogenic?

CRIPT p.Cys76Tyr (c.227G>A) is classified Pathogenic in CRIPT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with Rothmund-Thomson syndrome type 3.

What condition is associated with CRIPT p.Cys76Tyr (c.227G>A)?

CRIPT p.Cys76Tyr (c.227G>A) is associated with Rothmund-Thomson syndrome type 3 (ClinVar).

How common is CRIPT p.Cys76Tyr (c.227G>A) in the general population?

CRIPT p.Cys76Tyr (c.227G>A) is absent from gnomAD v4.1 (gnomAD).

How is Rothmund-Thomson syndrome inherited?

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

What do computational predictors say about CRIPT p.Cys76Tyr (c.227G>A)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

CRIPT p.Cys76Tyr

c.227G>A · rs2466595181 · VCV3233412

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,602,632)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rothmund-Thomson syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar · top 5% in CRIPT
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 6,941 bp · p 0.1 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,602,632). 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.Cys76Tyr
Coding: c.227G>A
MANE Select: NM_014171
dbSNP: rs2466595181
Type: single nucleotide variant
Location: chr2:46623853 (GRCh38)
Gene constraint: LOEUF 1.852 · pLI 0.19 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.77 · 1 PDB
Residue 76: an α-helix

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

For Rothmund-Thomson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CRIPT p.Cys76= Likely benign ★ same residue
CRIPT p.Ser64Phe Uncertain significance ★★ ⚠ same condition
CRIPT p.Cys3Tyr Likely pathogenic ★ same condition
CRIPT p.Cys58Ter Likely pathogenic ★ same condition
CRIPT c.242-19A>T Uncertain significance ★ same condition
CRIPT c.-422_17-582del Pathogenic ★ same condition
CRIPT p.Cys3fs Pathogenic ★ same condition
CRIPT p.Ala45fs 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-cys76tyr (accessed [today's date]).

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