Is SYN2 p.Arg500Trp (c.1498C>T) pathogenic?

SYN2 p.Arg500Trp (c.1498C>T) is classified Uncertain significance in SYN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1671); Ultra-rare (popmax 0.0166%, mid).

How common is SYN2 p.Arg500Trp (c.1498C>T) in the general population?

SYN2 p.Arg500Trp (c.1498C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about SYN2 p.Arg500Trp (c.1498C>T)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

SYN2 p.Arg500Trp

c.1498C>T · VCV4178481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.13, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 186 kb · p 0.66 · regional, not allelic
Overall
CADD	23.9	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 0.0166% Middle Eastern · 1/6,022 alleles

Filtering AF 0.00388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00354%

Overall 0.00412% 64/1,553,802 alleles · ultra-rare exomes 59/1,401,612 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,022
Remaining individualsnot grpmax-eligible	0.00663%	15,076
European (non-Finnish)	0.00497%	20,140
Admixed American	0.00195%	51,152
African / African-American	0.00137%	73,154

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: SYN2
Protein: p.Arg500Trp
Coding: c.1498C>T
MANE Select: NM_133625
Type: single nucleotide variant
Location: chr3:12187497 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 75.24
Residue 500: the 'disordered' region; the 'h; pro/ser-rich linker' region

Full SYN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYN2 p.Arg500Gln Uncertain significance ★ ⚠ same residue
SYN2 p.Arg500Leu Uncertain significance ★ ⚠ same residue
SYN2 p.Ala54Val Benign ★★ same type
SYN2 p.Thr506Ala Benign ★★ same type
SYN2 c.1369+21G>C Uncertain significance ★ same type
SYN2 p.Ala302Gly Uncertain significance ★ same type
SYN2 p.Ala546Gly Uncertain significance ★ ⚠ same type
SYN2 p.Arg179Gln 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/syn2-p-arg500trp (accessed [today's date]).

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