Is SYN1 p.Arg422Pro (c.1265G>C) pathogenic?

SYN1 p.Arg422Pro (c.1265G>C) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-13). AlphaMissense: likely benign (0.077); Absent from gnomAD v4.1.

How common is SYN1 p.Arg422Pro (c.1265G>C) in the general population?

SYN1 p.Arg422Pro (c.1265G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYN1 p.Arg422Pro (c.1265G>C)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

SYN1 p.Arg422Pro

c.1265G>C · rs2519685842 · VCV1878782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -3.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.18	phastCons 0.003
Regional constraint	o/e 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	14.74	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

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: SYN1
Protein: p.Arg422Pro
Coding: c.1265G>C
MANE Select: NM_006950
dbSNP: rs2519685842
Type: single nucleotide variant
Location: chrX:47575168 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 422: the 'disordered' region; the 'd; pro-rich linker' region

Full SYN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYN1 p.Arg422Ter Pathogenic ★★ same residue
SYN1 p.Arg422Gln Uncertain significance ★ ⚠ same residue
SYN1 p.Arg422= Likely benign ★ same residue
SYN1 c.528-2A>T Pathogenic/Likely pathogenic ★★ same type
SYN1 c.838-2A>G Likely pathogenic ★★ same type
SYN1 p.Arg234Ter Pathogenic ★★ same type
SYN1 p.Arg420Gln Likely pathogenic ★★ ⚠ same type
SYN1 p.Gln249Ter Pathogenic/Likely pathogenic ★★ 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/syn1-p-arg422pro (accessed [today's date]).

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