Is SYK p.Pro355= (c.1065C>T) pathogenic?

SYK p.Pro355= (c.1065C>T) is classified Benign in SYK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). Common (popmax 37.8%, amr) — too common for a highly-penetrant pathogenic allele.

SYK p.Pro355=

Q: How common is SYK p.Pro355= (c.1065C>T) in the general population?

SYK p.Pro355= (c.1065C>T) is common (popmax 37.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1065C>T · rs2290890 · VCV2688051

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 37.8%, amr) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.2
Overall
CADD	0.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.8% Admixed American · 22,694/59,978 alleles

Filtering AF 37.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.3%

Overall 15.7% 253,495/1,613,792 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	37.8%	3
Amishnot grpmax-eligible	34.5%	3
African / African-American	20.8%	5
East Asian	20.5%	5
Ashkenazi Jewishnot grpmax-eligible	20.4%	5
Finnishnot grpmax-eligible	19.7%	5
Remaining individualsnot grpmax-eligible	16.1%	6
European (non-Finnish)	14.1%	7
Middle Eastern	12.7%	8
South Asian	10.8%	9

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.Pro355=
Coding: c.1065C>T
MANE Select: NM_003177
dbSNP: rs2290890
Type: single nucleotide variant
Location: chr9:90874733 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.52 · 93 PDB
Residue 355: the 'interdomain b' region

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

Similar variants

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
SYK p.Asn499= 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-pro355 (accessed [today's date]).

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