Is CRIPTO p.Leu158= (c.474C>T) pathogenic?

CRIPTO p.Leu158= (c.474C>T) is classified Likely benign in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). Very rare (popmax 0.00223%, eas).

How common is CRIPTO p.Leu158= (c.474C>T) in the general population?

CRIPTO p.Leu158= (c.474C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

CRIPTO p.Leu158=

c.474C>T · VCV3771395

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.4	GERP -3.6
Overall
CADD	0.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,898 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
South Asian	0.0022%	45,535
European (non-Finnish)	0.000254%	393,331

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.Leu158=
Coding: c.474C>T
MANE Select: NM_003212
Type: single nucleotide variant
Location: chr3:46581157 (GRCh38)
Structure: AlphaFold pLDDT 67.47

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

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-leu158 (accessed [today's date]).

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