Is CRKL p.Pro18Ser (c.52C>T) pathogenic?

CRKL p.Pro18Ser (c.52C>T) is classified Uncertain significance in CRKL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.1174); Very rare (popmax 0.000339%, nfe).

How common is CRKL p.Pro18Ser (c.52C>T) in the general population?

CRKL p.Pro18Ser (c.52C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CRKL p.Pro18Ser (c.52C>T)?

AlphaMissense predicts likely benign (score 0.1174) — an in-silico prediction, not a clinical call.

CRKL p.Pro18Ser

c.52C>T · VCV3497174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1174 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1174	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 306 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	23.2	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 0.000339% European (non-Finnish) · 4/1,180,040 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,842 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: CRKL
Protein: p.Pro18Ser
Coding: c.52C>T
MANE Select: NM_005207
Type: single nucleotide variant
Location: chr22:20917986 (GRCh38)
Gene constraint: LOEUF 0.316 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 69.65 · 6 PDB
Residue 18: the sh2 domain; a β-strand

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-pro18ser (accessed [today's date]).

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