Is SYN1 p.Pro611Ser (c.1831C>T) pathogenic?

SYN1 p.Pro611Ser (c.1831C>T) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-29). AlphaMissense: likely benign (0.0654); Very rare (popmax 0.000121%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SYN1 p.Pro611Ser (c.1831C>T)?

SYN1 p.Pro611Ser (c.1831C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SYN1 p.Pro611Ser (c.1831C>T) in the general population?

SYN1 p.Pro611Ser (c.1831C>T) is very rare (popmax 0.000121%, nfe) (gnomAD).

What do computational predictors say about SYN1 p.Pro611Ser (c.1831C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

SYN1 p.Pro611Ser

c.1831C>T · rs1300239224 · VCV589838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000121%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.96	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 9.5	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,483 bp · p 0.025 · regional, not allelic
Overall
CADD	21.9	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

Grpmax group 0.000121% European (non-Finnish) · 1/828,605 alleles

Overall 0.000189% 2/1,059,790 alleles · very rare exomes 2/945,682 · genomes 0/114,108 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00242%	41,300
European (non-Finnish)grpmax	0.000121%	828,603

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SYN1
Protein: p.Pro611Ser
Coding: c.1831C>T
MANE Select: NM_006950
dbSNP: rs1300239224
Type: single nucleotide variant
Location: chrX:47574153 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 611: the 'disordered' region; a UniProt-annotated variant site (in xlid50; affects excitatory and inhibitory synaptic transmission leading to neuronal hyperexcitability; fails to rescue defective synaptic vesicle exocytosis in syn1-knockout mouse neurons; results in severely decreased phosphorylation by camk2 and mapk1; results in delayed axon elongation when tested in syn1-knockout mouse neurons; severely reduced interaction with syn2; has no effect on protein targeting to presynapse); the 'd; pro-rich linker' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SYN1 p.Ala441Asp Uncertain significance ★★ ⚠ same condition
SYN1 p.Arg169Trp Uncertain significance ★★ ⚠ same condition
SYN1 p.Arg424Trp Uncertain significance ★★ ⚠ same condition
SYN1 p.Gly320Ala Uncertain significance ★★ ⚠ same condition
SYN1 p.Gly440Arg Uncertain significance ★★ ⚠ same condition
SYN1 p.Gly47Arg Uncertain significance ★★ ⚠ same condition
SYN1 p.Gly571Ser Uncertain significance ★★ ⚠ same condition
SYN1 p.Gly608Cys Uncertain significance ★★ ⚠ same condition

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-pro611ser (accessed [today's date]).

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