Is CRIPT p.Cys3Tyr (c.8G>A) pathogenic?

CRIPT p.Cys3Tyr (c.8G>A) is classified Likely pathogenic in CRIPT (ClinVar, Single submitter, 2 submitters; last evaluated 2015-12-23). AlphaMissense: likely pathogenic (0.9919); Very rare (popmax 0.00272%, afr); Associated with Rothmund-Thomson syndrome type 3.

What condition is associated with CRIPT p.Cys3Tyr (c.8G>A)?

CRIPT p.Cys3Tyr (c.8G>A) is associated with Rothmund-Thomson syndrome type 3 (ClinVar).

How common is CRIPT p.Cys3Tyr (c.8G>A) in the general population?

CRIPT p.Cys3Tyr (c.8G>A) is very rare (popmax 0.00272%, afr) (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.Cys3Tyr (c.8G>A)?

AlphaMissense predicts likely pathogenic (score 0.9919) — an in-silico prediction, not a clinical call.

CRIPT p.Cys3Tyr

c.8G>A · rs757078301 · VCV221618

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rothmund-Thomson syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.9919	likely pathogenic ✓ concordant with ClinVar
REVEL	0.53	indeterminate
SaProt	LLR -13.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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

Grpmax group 0.00272% African / African-American · 2/73,622 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000129% 2/1,555,178 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CRIPT
Protein: p.Cys3Tyr
Coding: c.8G>A
MANE Select: NM_014171
dbSNP: rs757078301
Type: single nucleotide variant
Location: chr2:46617290 (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 3: a UniProt-annotated variant site (in rts3)

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.Cys3fs Pathogenic ★ same residue
CRIPT p.Ser64Phe Uncertain significance ★★ ⚠ same condition
CRIPT p.Cys58Ter Likely pathogenic ★ same condition
CRIPT c.242-19A>T Uncertain significance ★ same condition
CRIPT p.Cys76Tyr Pathogenic same condition
CRIPT c.-422_17-582del Pathogenic ★ same condition
CRIPT p.Ala45fs Pathogenic same condition
CRIPT p.Phe47fs 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-cys3tyr (accessed [today's date]).

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