Is CRIPTO p.Arg111Gly (c.331C>G) pathogenic?

CRIPTO p.Arg111Gly (c.331C>G) is classified Benign in CRIPTO (ClinVar, Multiple submitters, 4 submitters; last evaluated 2019-04-24). AlphaMissense: likely benign (0.2222); Common (popmax 6.56%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CRIPTO p.Arg111Gly (c.331C>G)?

AlphaMissense predicts likely benign (score 0.2222) — an in-silico prediction, not a clinical call.

CRIPTO p.Arg111Gly

Q: How common is CRIPTO p.Arg111Gly (c.331C>G) in the general population?

CRIPTO p.Arg111Gly (c.331C>G) is common (popmax 6.56%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.331C>G · rs34501971 · VCV778070

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2222 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.56%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2222	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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 2.5	GERP 0.69, phastCons 0.041
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	18.3	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 6.56% African / African-American · 4,918/74,962 alleles

Filtering AF 6.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.34%

Overall 0.338% 5,454/1,613,996 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.56%	15
Remaining individualsnot grpmax-eligible	0.397%	252
Admixed American	0.32%	313
Middle Eastern	0.266%	375
South Asian	0.0187%	5,358
European (non-Finnish)	0.00534%	18,731

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.Arg111Gly
Coding: c.331C>G
MANE Select: NM_003212
dbSNP: rs34501971
Type: single nucleotide variant
Location: chr3:46579846 (GRCh38)
Structure: AlphaFold pLDDT 67.47
Residue 111: a UniProt-annotated variant site (in)

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

Similar variants

CRIPTO p.Arg111His Uncertain significance ★ ⚠ same residue
CRIPTO c.339-8A>G Benign ★★ same type
CRIPTO p.Gly151= Benign/Likely benign ★★ 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
CRIPTO p.Arg62Pro 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-arg111gly (accessed [today's date]).

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