Is CRK p.Ser175Arg (c.525C>G) pathogenic?

CRK p.Ser175Arg (c.525C>G) is classified Uncertain significance in CRK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1976); Very rare (popmax 0.000424%, nfe).

How common is CRK p.Ser175Arg (c.525C>G) in the general population?

CRK p.Ser175Arg (c.525C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CRK p.Ser175Arg (c.525C>G)?

AlphaMissense predicts likely benign (score 0.1976) — an in-silico prediction, not a clinical call.

CRK p.Ser175Arg

c.525C>G · VCV4835709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1976	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP -1.4, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 147 bp · p 3.2e-08 · regional, not allelic
Overall
CADD	23.8	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 0.000424% European (non-Finnish) · 5/1,178,464 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,459,422 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: CRK
Protein: p.Ser175Arg
Coding: c.525C>G
MANE Select: NM_016823
Type: single nucleotide variant
Location: chr17:1436872 (GRCh38)
Gene constraint: LOEUF 0.337 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.09 · 10 PDB
Residue 175: the sh3 1 domain

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

Similar variants

CRK p.Arg68= Benign ★★ same type
CRK p.Tyr60= Benign ★★ same type
CRK p.Ala222Asp Uncertain significance ★ ⚠ same type
CRK p.Ala240Thr Uncertain significance ★ ⚠ same type
CRK p.Ala76Val Uncertain significance ★ ⚠ same type
CRK p.Arg10Trp Uncertain significance ★ ⚠ same type
CRK p.Arg283Gln Uncertain significance ★ ⚠ same type
CRK p.Arg292His 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/crk-p-ser175arg (accessed [today's date]).

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