Is SYN1 p.Pro472Ser (c.1414C>T) pathogenic?

SYN1 p.Pro472Ser (c.1414C>T) is classified Uncertain significance in SYN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-23). AlphaMissense: likely benign (0.0587); Very rare (popmax 0.000476%, nfe); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

What condition is associated with SYN1 p.Pro472Ser (c.1414C>T)?

SYN1 p.Pro472Ser (c.1414C>T) is associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Pro472Ser (c.1414C>T) in the general population?

SYN1 p.Pro472Ser (c.1414C>T) is very rare (popmax 0.000476%, nfe) (gnomAD).

What do computational predictors say about SYN1 p.Pro472Ser (c.1414C>T)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

SYN1 p.Pro472Ser

Q: How is X-linked epilepsy-learning disabilities-behavior disorders syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1414C>T · rs797046019 · VCV212331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000476%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -7.66	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 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	22.5	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 0.000476% European (non-Finnish) · 4/839,521 alleles

Filtering AF 0.000112% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.5e-05%

Overall 0.000364% 4/1,098,367 alleles · very rare exomes 4/984,853 · genomes 0/113,514 · 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.Pro472Ser
Coding: c.1414C>T
MANE Select: NM_006950
dbSNP: rs797046019
Type: single nucleotide variant
Location: chrX:47574570 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 472: the 'disordered' region; the 'd; pro-rich linker' region

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

Disease context

epilepsy, X-linked 1, with variable learning disabilities and behavior disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked epilepsy-learning disabilities-behavior disorders syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

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SYN1 p.Arg420Gln Likely pathogenic ★★ ⚠ same condition
SYN1 p.Arg422Ter Pathogenic ★★ same condition
SYN1 p.Gln483Ter Pathogenic ★★ same condition
SYN1 p.Gln555Ter Pathogenic ★★ same condition
SYN1 p.Glu121Ter Pathogenic/Likely pathogenic ★★ 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-pro472ser (accessed [today's date]).

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