Is CRKL p.Val178= (c.534C>T) pathogenic?

CRKL p.Val178= (c.534C>T) is classified Likely benign in CRKL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-12). Very rare (popmax 0.00439%, sas).

How common is CRKL p.Val178= (c.534C>T) in the general population?

CRKL p.Val178= (c.534C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

CRKL p.Val178=

c.534C>T · rs752182830 · VCV756908

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

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 -0.77	GERP -4.3, phastCons 0.01
Overall
CADD	4.707	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00143% 23/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00267%	37,460
European (non-Finnish)	0.00127%	78,669

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.Val178=
Coding: c.534C>T
MANE Select: NM_005207
dbSNP: rs752182830
Type: single nucleotide variant
Location: chr22:20934001 (GRCh38)
Gene constraint: LOEUF 0.316 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 69.65 · 6 PDB
Residue 178: the sh3 1 domain; a β-strand

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

Similar variants

CRKL p.Val178Ile Uncertain significance ★★ ⚠ same residue
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 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-val178 (accessed [today's date]).

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