Is CRISP2 p.Pro193Ala (c.577C>G) pathogenic?

CRISP2 p.Pro193Ala (c.577C>G) is classified Uncertain significance in CRISP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.1346); Very rare (popmax 0.00167%, amr).

How common is CRISP2 p.Pro193Ala (c.577C>G) in the general population?

CRISP2 p.Pro193Ala (c.577C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CRISP2 p.Pro193Ala (c.577C>G)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

CRISP2 p.Pro193Ala

c.577C>G · rs1487960903 · VCV2237263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -8.09	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 7.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 16 kb · p 0.063 · regional, not allelic
Overall
CADD	24.8	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 0.00167% Admixed American · 1/59,932 alleles

Overall 6.85e-05% 1/1,460,886 alleles · very rare

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: CRISP2
Protein: p.Pro193Ala
Coding: c.577C>G
MANE Select: NM_003296
dbSNP: rs1487960903
Type: single nucleotide variant
Location: chr6:49695863 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.33 · 1 PDB
Residue 193: a disulfide bond

Full CRISP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRISP2 c.66+6G>C Likely benign ★★ same type
CRISP2 p.Pro53= Likely benign ★★ same type
CRISP2 p.Ala234Thr Uncertain significance ★ ⚠ same type
CRISP2 p.Arg178Thr Uncertain significance ★ ⚠ same type
CRISP2 p.Arg38Gly Uncertain significance ★ ⚠ same type
CRISP2 p.Asn177Asp Uncertain significance ★ ⚠ same type
CRISP2 p.Asn76Ser Uncertain significance ★ ⚠ same type
CRISP2 p.Asp215His 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/crisp2-p-pro193ala (accessed [today's date]).

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