Is CRIPT p.Cys86Phe (c.257G>T) pathogenic?

CRIPT p.Cys86Phe (c.257G>T) is classified Uncertain significance in CRIPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-21). AlphaMissense: likely pathogenic (0.997); Very rare (popmax 8.61e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRIPT p.Cys86Phe (c.257G>T)?

CRIPT p.Cys86Phe (c.257G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRIPT p.Cys86Phe (c.257G>T) in the general population?

CRIPT p.Cys86Phe (c.257G>T) is very rare (popmax 8.61e-05%, nfe) (gnomAD).

What do computational predictors say about CRIPT p.Cys86Phe (c.257G>T)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

CRIPT p.Cys86Phe

c.257G>T · rs2466595918 · VCV2184694

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.61e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic · top 6% in CRIPT
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -16.70	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 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 6,941 bp · p 0.1 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.61e-05% European (non-Finnish) · 1/1,161,062 alleles

Overall 6.99e-05% 1/1,430,556 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.Cys86Phe
Coding: c.257G>T
MANE Select: NM_014171
dbSNP: rs2466595918
Type: single nucleotide variant
Location: chr2:46624178 (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 86: a turn

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

Similar variants

CRIPT p.Ala45Pro Uncertain significance ★★ ⚠ same condition
CRIPT p.Ala84Val 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.Ser64Phe Uncertain significance ★★ ⚠ same condition
CRIPT p.Ala39Val Uncertain significance ★ ⚠ same condition
CRIPT p.Arg59Gly Uncertain significance ★ ⚠ 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-cys86phe (accessed [today's date]).

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