Is CRIPT p.Ser64Phe (c.191C>T) pathogenic?

CRIPT p.Ser64Phe (c.191C>T) is classified Uncertain significance in CRIPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-20). AlphaMissense: ambiguous (0.4489); Very rare (popmax 0.00721%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRIPT p.Ser64Phe (c.191C>T)?

CRIPT p.Ser64Phe (c.191C>T) is associated with Inborn genetic diseases, Rothmund-Thomson syndrome type 3 (ClinVar).

How common is CRIPT p.Ser64Phe (c.191C>T) in the general population?

CRIPT p.Ser64Phe (c.191C>T) is very rare (popmax 0.00721%, nfe) (gnomAD).

What do computational predictors say about CRIPT p.Ser64Phe (c.191C>T)?

AlphaMissense predicts ambiguous (score 0.4489) — an in-silico prediction, not a clinical call.

CRIPT p.Ser64Phe

c.191C>T · VCV3586711

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4489	ambiguous
REVEL	0.473	indeterminate
SaProt	LLR -11.91	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 6,941 bp · p 0.1 · regional, not allelic
Overall
CADD	29.7	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 0.00721% European (non-Finnish) · 85/1,178,298 alleles

Filtering AF 0.00597% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.0054% 87/1,610,892 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00721%	13,862
Remaining individualsnot grpmax-eligible	0.0016%	62,336
African / African-American	0.00134%	74,764

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.Ser64Phe
Coding: c.191C>T
MANE Select: NM_014171
Type: single nucleotide variant
Location: chr2:46623817 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rothmund-Thomson syndrome type 3

Similar variants

CRIPT p.Ala45Pro Uncertain significance ★★ ⚠ same condition
CRIPT p.Ala84Val Uncertain significance ★★ ⚠ same condition
CRIPT p.Cys86Phe Uncertain significance ★★ ⚠ same condition
CRIPT p.Gln74Arg Uncertain significance ★★ ⚠ same condition
CRIPT p.Gly81Val Uncertain significance ★★ ⚠ same condition
CRIPT p.Lys88Arg Uncertain significance ★★ ⚠ 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-ser64phe (accessed [today's date]).

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