Is CRIPTO p.Asp109His (c.325G>C) pathogenic?

CRIPTO p.Asp109His (c.325G>C) is classified Likely benign in CRIPTO (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-26). AlphaMissense: likely pathogenic (0.5641); Ultra-rare (popmax 0.0603%, nfe).

How common is CRIPTO p.Asp109His (c.325G>C) in the general population?

CRIPTO p.Asp109His (c.325G>C) is ultra-rare (popmax 0.0603%, nfe) (gnomAD).

What do computational predictors say about CRIPTO p.Asp109His (c.325G>C)?

AlphaMissense predicts likely pathogenic (score 0.5641) — an in-silico prediction, not a clinical call.

CRIPTO p.Asp109His

c.325G>C · rs148619685 · VCV618419

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0603%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5641	likely pathogenic
REVEL	0.286	benign-leaning
SaProt	LLR -11.25	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.33, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,277 bp · p 0.14 · regional, not allelic
Overall
CADD	17.42	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 0.0603% European (non-Finnish) · 712/1,180,044 alleles

Filtering AF 0.0566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0552%

Overall 0.0556% 898/1,614,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.206%	485
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
European (non-Finnish)grpmax	0.0603%	1,657
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Admixed American	0.0117%	8,576
African / African-American	0.00533%	18,763
South Asian	0.0011%	91,084

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp109His
Coding: c.325G>C
MANE Select: NM_003212
dbSNP: rs148619685
Type: single nucleotide variant
Location: chr3:46579840 (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-asp109his (accessed [today's date]).

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