Is CRIPTO p.Tyr43Asp (c.127T>G) pathogenic?

CRIPTO p.Tyr43Asp (c.127T>G) is classified Benign in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-29). AlphaMissense: likely benign (0.0379); Common (popmax 16.5%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CRIPTO p.Tyr43Asp (c.127T>G)?

AlphaMissense predicts likely benign (score 0.0379) — an in-silico prediction, not a clinical call.

CRIPTO p.Tyr43Asp

Q: How common is CRIPTO p.Tyr43Asp (c.127T>G) in the general population?

CRIPTO p.Tyr43Asp (c.127T>G) is common (popmax 16.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.127T>G · rs2293025 · VCV1280750

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0379 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0379	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -5.42	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 1.9	GERP -2.8, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	6.29	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 16.5% East Asian · 7,400/44,878 alleles

Filtering AF 16.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 16%

Overall 4.03% 65,025/1,614,158 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	16.5%	6
South Asian	14.3%	7
Middle Eastern	8.31%	12
Amishnot grpmax-eligible	7.13%	14
Admixed American	5.48%	18
Remaining individualsnot grpmax-eligible	4.66%	21
Finnishnot grpmax-eligible	3.91%	26
Ashkenazi Jewishnot grpmax-eligible	3.27%	31
European (non-Finnish)	2.85%	35
African / African-American	0.934%	107

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.Tyr43Asp
Coding: c.127T>G
MANE Select: NM_003212
dbSNP: rs2293025
Type: single nucleotide variant
Location: chr3:46579270 (GRCh38)
Structure: AlphaFold pLDDT 67.47
Residue 43: a UniProt-annotated variant site (in)

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-tyr43asp (accessed [today's date]).

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