Is CRIPTO p.Pro39Thr (c.115C>A) pathogenic?

CRIPTO p.Pro39Thr (c.115C>A) is classified Uncertain significance in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). AlphaMissense: likely benign (0.1037); Very rare (popmax 0.00533%, afr); Associated with CRIPTO-related disorder.

What condition is associated with CRIPTO p.Pro39Thr (c.115C>A)?

CRIPTO p.Pro39Thr (c.115C>A) is associated with CRIPTO-related disorder (ClinVar).

How common is CRIPTO p.Pro39Thr (c.115C>A) in the general population?

CRIPTO p.Pro39Thr (c.115C>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CRIPTO p.Pro39Thr (c.115C>A)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

CRIPTO p.Pro39Thr

c.115C>A · rs1215656011 · VCV2633749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRIPTO-related disorder

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.34	GERP 0.84
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	6.773	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00533% African / African-American · 4/75,036 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,132 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: CRIPTO
Protein: p.Pro39Thr
Coding: c.115C>A
MANE Select: NM_003212
dbSNP: rs1215656011
Type: single nucleotide variant
Location: chr3:46579258 (GRCh38)
Structure: AlphaFold pLDDT 67.47

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

Disease context

CRIPTO-related disorder

Similar variants

CRIPTO c.339-8A>G Benign ★★ same type
CRIPTO p.Arg111Gly Benign ★★ ⚠ same type
CRIPTO p.Gly151= Benign/Likely benign ★★ same type
CRIPTO p.Arg111His Uncertain significance ★ ⚠ same type
CRIPTO p.Arg171His Uncertain significance ★ ⚠ same type
CRIPTO p.Arg38Cys Uncertain significance ★ ⚠ same type
CRIPTO p.Arg38His Uncertain significance ★ ⚠ same type
CRIPTO p.Arg60Gln Uncertain significance ★ ⚠ same type

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/cripto-p-pro39thr (accessed [today's date]).

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