Is CRIPTO p.Val22Ala (c.65T>C) pathogenic?

CRIPTO p.Val22Ala (c.65T>C) is classified Benign in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-27). AlphaMissense: likely benign (0.0529); Common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CRIPTO p.Val22Ala (c.65T>C)?

AlphaMissense predicts likely benign (score 0.0529) — an in-silico prediction, not a clinical call.

CRIPTO p.Val22Ala

Q: How common is CRIPTO p.Val22Ala (c.65T>C) in the general population?

CRIPTO p.Val22Ala (c.65T>C) is common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.65T>C · rs11130097 · VCV1275194

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0529 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 59.2%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0529	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.35	GERP -3.4
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	0.934	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 59.2% South Asian · 53,883/91,072 alleles

Filtering AF 58.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 58.6%

Overall 52.6% 848,123/1,613,650 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	59.2%	2
Middle Eastern	58.9%	2
European (non-Finnish)	53.4%	2
Amishnot grpmax-eligible	52.6%	2
Finnishnot grpmax-eligible	51.9%	2
Remaining individualsnot grpmax-eligible	51.4%	2
African / African-American	48.6%	2
Ashkenazi Jewishnot grpmax-eligible	46.1%	2
Admixed American	45.2%	2
East Asian	40.3%	2

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.Val22Ala
Coding: c.65T>C
MANE Select: NM_003212
dbSNP: rs11130097
Type: single nucleotide variant
Location: chr3:46579124 (GRCh38)
Structure: AlphaFold pLDDT 67.47
Residue 22: a UniProt-annotated variant site (in)

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

Similar variants

CRIPTO p.Val22= Likely benign ★ same residue
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

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-val22ala (accessed [today's date]).

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