Is CRKL p.His187= (c.561C>T) pathogenic?

CRKL p.His187= (c.561C>T) is classified Likely benign in CRKL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). Ultra-rare (popmax 0.0217%, nfe).

How common is CRKL p.His187= (c.561C>T) in the general population?

CRKL p.His187= (c.561C>T) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

CRKL p.His187=

c.561C>T · VCV3633567

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

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 -6.1	GERP -5.3
Overall
CADD	1.757	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% European (non-Finnish) · 256/1,180,048 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0167% 269/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0217%	4,610
Middle Eastern	0.0164%	6,084
East Asian	0.00668%	14,964
Admixed American	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0048%	20,830
African / African-American	0.004%	24,970

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: CRKL
Protein: p.His187=
Coding: c.561C>T
MANE Select: NM_005207
Type: single nucleotide variant
Location: chr22:20934028 (GRCh38)
Gene constraint: LOEUF 0.316 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 69.65 · 6 PDB
Residue 187: the 'disordered' region

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

Similar variants

CRKL p.Ala226Val Uncertain significance ★★ ⚠ same type
CRKL p.Arg169Gln Uncertain significance ★★ ⚠ same type
CRKL p.Asn137Ser Uncertain significance ★★ ⚠ same type
CRKL p.Ile263Thr Uncertain significance ★★ ⚠ same type
CRKL p.Val178Ile Uncertain significance ★★ ⚠ same type
CRKL c.311+12C>T Likely benign ★★ same type
CRKL p.Gly221Ser Benign ★★ same type
CRKL p.Ser12= Benign ★★ 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/crkl-p-his187 (accessed [today's date]).

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