Is SYNCRIP p.Arg557Cys (c.1669C>T) pathogenic?

SYNCRIP p.Arg557Cys (c.1669C>T) is classified Uncertain significance in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.9053); Very rare (popmax 0.00119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SYNCRIP p.Arg557Cys (c.1669C>T)?

SYNCRIP p.Arg557Cys (c.1669C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SYNCRIP p.Arg557Cys (c.1669C>T) in the general population?

SYNCRIP p.Arg557Cys (c.1669C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about SYNCRIP p.Arg557Cys (c.1669C>T)?

AlphaMissense predicts likely pathogenic (score 0.9053) — an in-silico prediction, not a clinical call.

SYNCRIP p.Arg557Cys

c.1669C>T · VCV4632506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9053	likely pathogenic
REVEL	0.34	indeterminate
SaProt	LLR -12.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 325 bp · p 0.12 · regional, not allelic
Overall
CADD	34.0	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 0.00119% European (non-Finnish) · 14/1,179,892 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00093% 15/1,613,664 alleles · very rare exomes 14/1,461,654 · genomes 1/152,010 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,278
South Asian	0.0011%	91,044

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.Arg557Cys
Coding: c.1669C>T
MANE Select: NM_006372
Type: single nucleotide variant
Location: chr6:85614959 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 557: the 'interaction with apobec1' region; the '8 x 3 aa repeats of r-g-g' region; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SYNCRIP p.Ala216Thr Uncertain significance ★★ same condition
SYNCRIP p.Asn243Ser Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Pro440Leu Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Pro508Leu Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Ser116Gly Uncertain significance ★★ ⚠ same condition
SYNCRIP p.Glu612Val Likely benign ★★ ⚠ same condition
SYNCRIP p.Ala346Thr Uncertain significance ★ ⚠ same condition
SYNCRIP p.Ala357Val Uncertain significance ★ ⚠ 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/syncrip-p-arg557cys (accessed [today's date]).

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