Is SYNCRIP p.Gly522Cys (c.1564G>T) pathogenic?

SYNCRIP p.Gly522Cys (c.1564G>T) is classified Uncertain significance in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-28). AlphaMissense: likely benign (0.1596); Very rare (popmax 0.005%, amr).

How common is SYNCRIP p.Gly522Cys (c.1564G>T) in the general population?

SYNCRIP p.Gly522Cys (c.1564G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about SYNCRIP p.Gly522Cys (c.1564G>T)?

AlphaMissense predicts likely benign (score 0.1596) — an in-silico prediction, not a clinical call.

SYNCRIP p.Gly522Cys

c.1564G>T · VCV4884969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1596	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -13.38	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 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 325 bp · p 0.12 · regional, not allelic
Overall
CADD	33.0	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 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,074 alleles · very rare exomes 3/1,461,886 · genomes 0/152,188 · 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: SYNCRIP
Protein: p.Gly522Cys
Coding: c.1564G>T
MANE Select: NM_006372
Type: single nucleotide variant
Location: chr6:85615064 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 522: the 'interaction with apobec1' region; the '8 x 3 aa repeats of r-g-g' region; the 'disordered' region; the 'interaction with smn' region

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

Similar variants

SYNCRIP p.Gly522Ser Uncertain significance ★ ⚠ same residue
SYNCRIP p.Gly522fs Uncertain significance ★ same residue
SYNCRIP p.Ala216Thr Uncertain significance ★★ same type
SYNCRIP p.Asn243Ser Uncertain significance ★★ ⚠ same type
SYNCRIP p.Pro440Leu Uncertain significance ★★ ⚠ same type
SYNCRIP p.Pro508Leu Uncertain significance ★★ ⚠ same type
SYNCRIP p.Ser116Gly Uncertain significance ★★ ⚠ same type
SYNCRIP p.Glu612Val Likely benign ★★ ⚠ 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/syncrip-p-gly522cys (accessed [today's date]).

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