Is SYN2 p.Glu408Ter (c.1222G>T) pathogenic?

SYN2 p.Glu408Ter (c.1222G>T) is classified Uncertain significance in SYN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-06). Absent from gnomAD v4.1.

How common is SYN2 p.Glu408Ter (c.1222G>T) in the general population?

SYN2 p.Glu408Ter (c.1222G>T) is absent from gnomAD v4.1 (gnomAD).

SYN2 p.Glu408Ter

c.1222G>T · VCV4961350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 13
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SYN2
Protein: p.Glu408Ter
Coding: c.1222G>T
MANE Select: NM_133625
Type: single nucleotide variant
Location: chr3:12169820 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 75.24
Residue 408: the 'c; actin-binding and synaptic-vesicle binding' region

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

Similar variants

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
SYN2 p.Arg186Gln Uncertain significance ★ ⚠ same type
SYN2 p.Arg315Trp 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-glu408ter (accessed [today's date]).

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