Is CRIPTO p.Gln143Arg (c.428A>G) pathogenic?

CRIPTO p.Gln143Arg (c.428A>G) is classified Uncertain significance in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1817); Very rare (popmax 0.00133%, afr).

How common is CRIPTO p.Gln143Arg (c.428A>G) in the general population?

CRIPTO p.Gln143Arg (c.428A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CRIPTO p.Gln143Arg (c.428A>G)?

AlphaMissense predicts likely benign (score 0.1817) — an in-silico prediction, not a clinical call.

CRIPTO p.Gln143Arg

c.428A>G · VCV4006868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1817	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, 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 0.00133% African / African-American · 1/74,946 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,946
European (non-Finnish)	0.000508%	196,670

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.Gln143Arg
Coding: c.428A>G
MANE Select: NM_003212
Type: single nucleotide variant
Location: chr3:46580040 (GRCh38)
Structure: AlphaFold pLDDT 67.47
Residue 143: a disulfide bond

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-gln143arg (accessed [today's date]).

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