Is SYNJ2 p.Ala593Ser (c.1777G>T) pathogenic?

SYNJ2 p.Ala593Ser (c.1777G>T) is classified Uncertain significance in SYNJ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: ambiguous (0.4176); Ultra-rare (popmax 0.0223%, eas).

How common is SYNJ2 p.Ala593Ser (c.1777G>T) in the general population?

SYNJ2 p.Ala593Ser (c.1777G>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about SYNJ2 p.Ala593Ser (c.1777G>T)?

AlphaMissense predicts ambiguous (score 0.4176) — an in-silico prediction, not a clinical call.

SYNJ2 p.Ala593Ser

c.1777G>T · VCV3323956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Computational evidence

Protein change
AlphaMissense	0.4176	ambiguous
REVEL	0.411	indeterminate
SaProt	LLR -10.53	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 114 kb · p 0.16 · regional, not allelic
Overall
CADD	28.8	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 0.0223% East Asian · 10/44,890 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000619% 10/1,614,210 alleles · ultra-rare exomes 10/1,461,852 · genomes 0/152,358 · 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: SYNJ2
Protein: p.Ala593Ser
Coding: c.1777G>T
MANE Select: NM_003898
Type: single nucleotide variant
Location: chr6:158068706 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.47 · 1 PDB
Residue 593: the 5-ppase domain

Full SYNJ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYNJ2 p.Ala593Thr Uncertain significance ★ same residue
SYNJ2 p.Asp1071Glu Uncertain significance ★★ ⚠ same type
SYNJ2 p.Val420Ala Likely benign ★★ same type
SYNJ2 p.Ala1072Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala111Asp Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1186Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1199Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1274Gly Uncertain significance ★ ⚠ 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/synj2-p-ala593ser (accessed [today's date]).

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