Is SYK p.Arg520Ser (c.1558C>A) pathogenic?

SYK p.Arg520Ser (c.1558C>A) is classified Conflicting classifications of pathogenicity in SYK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.2218); Ultra-rare (popmax 0.0433%, nfe).

How common is SYK p.Arg520Ser (c.1558C>A) in the general population?

SYK p.Arg520Ser (c.1558C>A) is ultra-rare (popmax 0.0433%, nfe) (gnomAD).

What do computational predictors say about SYK p.Arg520Ser (c.1558C>A)?

AlphaMissense predicts likely benign (score 0.2218) — an in-silico prediction, not a clinical call.

SYK p.Arg520Ser

c.1558C>A · rs200320837 · VCV2341397

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2218	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -4.69	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 -0.091	GERP -2.9
Regional constraint	o/e 0.55	unconstrained · MANE · 21 kb · p 7e-19 · regional, not allelic
Overall
CADD	12.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% European (non-Finnish) · 510/1,177,884 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.0328% 528/1,611,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0433%	2,310
Remaining individualsnot grpmax-eligible	0.0144%	6,931
African / African-American	0.00534%	18,726
Admixed American	0.005%	19,992
Finnishnot grpmax-eligible	0.00313%	31,991

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: SYK
Protein: p.Arg520Ser
Coding: c.1558C>A
MANE Select: NM_003177
dbSNP: rs200320837
Type: single nucleotide variant
Location: chr9:90878930 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.52 · 93 PDB
Residue 520: the protein kinase domain

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

Similar variants

SYK p.Arg520His Likely benign ★ same residue
SYK p.Glu473Gln Uncertain significance ★★ ⚠ same type
SYK c.1182-4G>A Benign ★★ same type
SYK c.1182-7C>A Benign ★★ same type
SYK c.1182-7C>G Benign ★★ same type
SYK c.1582-16T>A Benign ★★ same type
SYK c.796+20G>C Benign/Likely benign ★★ same type
SYK p.Arg434= 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/syk-p-arg520ser (accessed [today's date]).

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