Is SYN1 p.Ser62Phe (c.185C>T) pathogenic?

SYN1 p.Ser62Phe (c.185C>T) is classified Uncertain significance in SYN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-07). AlphaMissense: likely benign (0.2318); Ultra-rare (popmax 0.0401%, sas); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

How common is SYN1 p.Ser62Phe (c.185C>T) in the general population?

SYN1 p.Ser62Phe (c.185C>T) is ultra-rare (popmax 0.0401%, sas) (gnomAD).

What do computational predictors say about SYN1 p.Ser62Phe (c.185C>T)?

AlphaMissense predicts likely benign (score 0.2318) — an in-silico prediction, not a clinical call.

SYN1 p.Ser62Phe

Q: What condition is associated with SYN1 p.Ser62Phe (c.185C>T)?

SYN1 p.Ser62Phe (c.185C>T) is associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

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.185C>T · rs776054489 · VCV1974021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2318 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.2318	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% South Asian · 22/54,931 alleles

Filtering AF 0.027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00202% 24/1,189,388 alleles · ultra-rare exomes 24/1,075,871 · genomes 0/113,517 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0401%	2,497
Remaining individualsnot grpmax-eligible	0.00214%	46,712
African / African-American	0.00176%	56,974

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.Ser62Phe
Coding: c.185C>T
MANE Select: NM_006950
dbSNP: rs776054489
Type: single nucleotide variant
Location: chrX:47619544 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 62: the 'disordered' region; a modified residue (phosphoserine); the 'b; 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

SYN1 p.Ser62Ala Uncertain significance ★ ⚠ same residue
SYN1 c.528-2A>T Pathogenic/Likely pathogenic ★★ same condition
SYN1 c.838-2A>G Likely pathogenic ★★ same condition
SYN1 p.Arg234Ter Pathogenic ★★ same condition
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

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-ser62phe (accessed [today's date]).

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