Is SYNJ2 p.Arg520His (c.1559G>A) pathogenic?

SYNJ2 p.Arg520His (c.1559G>A) is classified Uncertain significance in SYNJ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1871); Rare (popmax 0.467%, sas).

How common is SYNJ2 p.Arg520His (c.1559G>A) in the general population?

SYNJ2 p.Arg520His (c.1559G>A) is rare (popmax 0.467%, sas) (gnomAD).

What do computational predictors say about SYNJ2 p.Arg520His (c.1559G>A)?

AlphaMissense predicts likely benign (score 0.1871) — an in-silico prediction, not a clinical call.

SYNJ2 p.Arg520His

c.1559G>A · VCV4178689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1871 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.467%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1871	likely benign
REVEL	0.642	indeterminate
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 114 kb · p 0.16 · regional, not allelic
Overall
CADD	34.0	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 0.467% South Asian · 425/91,076 alleles

Filtering AF 0.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.416%

Overall 0.0317% 511/1,614,106 alleles · rare exomes 489/1,461,886 · genomes 22/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.467%	214
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.035%	2,857
East Asian	0.0134%	7,481
European (non-Finnish)	0.00246%	40,691
African / African-American	0.00133%	75,010

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.Arg520His
Coding: c.1559G>A
MANE Select: NM_003898
Type: single nucleotide variant
Location: chr6:158066477 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.47 · 1 PDB

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

Similar variants

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
SYNJ2 p.Ala1298Ser 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-arg520his (accessed [today's date]).

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