Is SYN1 p.Ala604Val (c.1811C>T) pathogenic?

SYN1 p.Ala604Val (c.1811C>T) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1099); Very rare (popmax 0.00198%, afr); Associated with Inborn genetic diseases.

What condition is associated with SYN1 p.Ala604Val (c.1811C>T)?

SYN1 p.Ala604Val (c.1811C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SYN1 p.Ala604Val (c.1811C>T) in the general population?

SYN1 p.Ala604Val (c.1811C>T) is very rare (popmax 0.00198%, afr) (gnomAD).

What do computational predictors say about SYN1 p.Ala604Val (c.1811C>T)?

AlphaMissense predicts likely benign (score 0.1099) — an in-silico prediction, not a clinical call.

SYN1 p.Ala604Val

c.1811C>T · VCV4632499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00198%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1099	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.44	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 9.1	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,483 bp · p 0.025 · regional, not allelic
Overall
CADD	24.3	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 0.00198% African / African-American · 1/50,585 alleles

Overall 9.49e-05% 1/1,053,249 alleles · very rare exomes 0/940,299 · genomes 1/112,950 · joint denominator

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.Ala604Val
Coding: c.1811C>T
MANE Select: NM_006950
Type: single nucleotide variant
Location: chrX:47574173 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 604: 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-ala604val (accessed [today's date]).

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