Is CRISP2 p.Pro53= (c.159A>G) pathogenic?

CRISP2 p.Pro53= (c.159A>G) is classified Likely benign in CRISP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-16). Common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele.

CRISP2 p.Pro53=

Q: How common is CRISP2 p.Pro53= (c.159A>G) in the general population?

CRISP2 p.Pro53= (c.159A>G) is common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.159A>G · rs57295760 · VCV776128

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.2	GERP -3.6
Overall
CADD	8.154	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.1% African / African-American · 9,014/74,492 alleles

Filtering AF 11.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.8%

Overall 0.664% 10,612/1,598,364 alleles · common exomes 5,544/1,446,324 · genomes 5,068/152,040 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.1%	8
Middle Eastern	1.25%	80
Remaining individualsnot grpmax-eligible	0.892%	112
Admixed American	0.763%	131
Ashkenazi Jewishnot grpmax-eligible	0.174%	574
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)	0.0379%	2,640
South Asian	0.0366%	2,732
Finnishnot grpmax-eligible	0.00161%	61,948

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.Pro53=
Coding: c.159A>G
MANE Select: NM_003296
dbSNP: rs57295760
Type: single nucleotide variant
Location: chr6:49700692 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.33 · 1 PDB
Residue 53: the scp domain

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.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
CRISP2 p.Cys155Arg 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-pro53 (accessed [today's date]).

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