Is SYN1 p.Phe148Ser (c.443T>C) pathogenic?

SYN1 p.Phe148Ser (c.443T>C) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 0.000112%, nfe).

How common is SYN1 p.Phe148Ser (c.443T>C) in the general population?

SYN1 p.Phe148Ser (c.443T>C) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about SYN1 p.Phe148Ser (c.443T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

SYN1 p.Phe148Ser

c.443T>C · VCV3337644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 2% in SYN1
REVEL	0.651	pathogenic-leaning
SaProt	LLR -14.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000112% European (non-Finnish) · 1/894,956 alleles

Overall 8.27e-05% 1/1,209,174 alleles · very rare exomes 0/1,097,864 · genomes 1/111,310 · 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.Phe148Ser
Coding: c.443T>C
MANE Select: NM_006950
Type: single nucleotide variant
Location: chrX:47607029 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 148: the 'c; actin-binding and synaptic-vesicle binding' region

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

Similar variants

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.Arg422Ter Pathogenic ★★ same type
SYN1 p.Gln249Ter Pathogenic/Likely pathogenic ★★ same type
SYN1 p.Gln483Ter Pathogenic ★★ same type
SYN1 p.Gln555Ter 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-phe148ser (accessed [today's date]).

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