Is CRKL p.Asn280= (c.840C>T) pathogenic?

CRKL p.Asn280= (c.840C>T) is classified Conflicting classifications of pathogenicity in CRKL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). Ultra-rare (popmax 0.0133%, afr).

How common is CRKL p.Asn280= (c.840C>T) in the general population?

CRKL p.Asn280= (c.840C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

CRKL p.Asn280=

c.840C>T · rs769606385 · VCV626092

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

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 -2.5	GERP -2.3
Overall
CADD	9.239	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,966 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00211% 34/1,612,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,497
East Asian	0.00447%	22,390
Remaining individualsnot grpmax-eligible	0.0032%	31,239
South Asian	0.0022%	45,393
Admixed American	0.00167%	59,820
European (non-Finnish)	0.00144%	69,385

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.Asn280=
Coding: c.840C>T
MANE Select: NM_005207
dbSNP: rs769606385
Type: single nucleotide variant
Location: chr22:20949773 (GRCh38)
Gene constraint: LOEUF 0.316 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 69.65 · 6 PDB
Residue 280: the sh3 2 domain

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-asn280 (accessed [today's date]).

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