Is CRIPTO p.Pro125Leu (c.374C>T) pathogenic?

CRIPTO p.Pro125Leu (c.374C>T) is classified Uncertain significance in CRIPTO (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-05-01). AlphaMissense: likely benign (0.2033); Ultra-rare (popmax 0.0299%, nfe); Associated with Forebrain defects.

What condition is associated with CRIPTO p.Pro125Leu (c.374C>T)?

CRIPTO p.Pro125Leu (c.374C>T) is associated with Forebrain defects (ClinVar).

How common is CRIPTO p.Pro125Leu (c.374C>T) in the general population?

CRIPTO p.Pro125Leu (c.374C>T) is ultra-rare (popmax 0.0299%, nfe) (gnomAD).

What do computational predictors say about CRIPTO p.Pro125Leu (c.374C>T)?

AlphaMissense predicts likely benign (score 0.2033) — an in-silico prediction, not a clinical call.

CRIPTO p.Pro125Leu

c.374C>T · rs121909501 · VCV12728

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2033 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0299%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Forebrain defects

Computational evidence

Protein change
AlphaMissense	0.2033	likely benign
REVEL	0.607	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	24.5	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 0.0299% European (non-Finnish) · 353/1,180,052 alleles

Filtering AF 0.0273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.0245% 395/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0406%	2,463
European (non-Finnish)grpmax	0.0299%	3,343
Remaining individualsnot grpmax-eligible	0.0096%	10,414
South Asian	0.00659%	15,180
African / African-American	0.00534%	18,737

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro125Leu
Coding: c.374C>T
MANE Select: NM_003212
dbSNP: rs121909501
Type: single nucleotide variant
Location: chr3:46579986 (GRCh38)
Structure: AlphaFold pLDDT 67.47
Residue 125: a disulfide bond

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

Disease context

Forebrain defects — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro125leu (accessed [today's date]).

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