SYNCRIP

protein-coding

synaptotagmin binding cytoplasmic RNA interacting protein, the group of RNA binding motif containing|Heterogeneous nuclear ribonucleoproteins

Gene summary

This gene encodes a member of the cellular heterogeneous nuclear ribonucleoprotein (hnRNP) family. hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA (hnRNA) and regulate alternative splicing, polyadenylation, and other aspects of mRNA metabolism and transport. The encoded protein plays a role in multiple aspects of mRNA maturation and is associated with several multiprotein complexes including the apoB RNA editing-complex and survival of motor neurons (SMN) complex. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 20. [provided by RefSeq, Dec 2011]

MANE transcript

NM_006372.5

Inheritance

ClinVar variants

P:5U:119B:12

Top phenotype

SYNCRIP-related neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr6:85,607,779-85,644,063

External References & Databases

Ensembl (ENSG00000135316)

Transcript & Mutation Effects

hg38 • Region Span ~36.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SYNCRIP-related neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0800456

Submitter: G2P

SYNCRIP-related neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800456

Submitter: ClinGen

*SYNCRIP* encodes a nuclear ribonucleoprotein implicated in mRNA processing mechanisms. *SYNCRIP* was first reported in relation to autosomal dominant SYNCRIP-related neurodevelopmental disorder in 2021 (Gillentine et al., PMID: 33874999). The disorder is characterized by developmental delay, intellectual disability, speech and language delay, behavioral abnormalities including autism spectrum disorder, brain imaging abnormalities, hypotonia, seizures, and dysmorphic facial features (PMID: 3387499, doi.org/10.1016/j.rare.2024.100052). Other less frequent features include eye abnormalities, hand and feet abnormalities, skeletal abnormalities, growth delay, and genitourinary abnormalities. Sixteen variants (frameshift and nonsense) that have been reported in 17 probands in four publications (PMIDs: 23020937, 27479843, 33874999, 34157790) are included in this curation. Variants were *de novo* in all instances in which parental DNA was available. Of note, 7 variants occurred in the penultimate or last exon and are expected to escape nonsense-mediated RNA decay; however, at least one nonsense variant in the last exon was shown to result in nonsense mediated decay as opposed to truncation (doi.org/10.1016/j.rare.2024.100052). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *De novo* missense variants in *SYNCRIP* have also been reported in individuals with autism or other neurodevelopmental disorders (PMIDs: 30504930, 33057194, 33874999, 34157790). However, given the absence of functional evidence of pathogenicity, these variants were not scored. *SYNCRIP* is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.25, gnomAD v4.1.0) and missense variants (Z = 4.85). The mechanism of pathogenicity appears to be loss of function (PMIDs: 33874999, 39776340). This gene-disease relationship is also supported by biochemical function, protein interaction, and a mouse model showing that loss of Syncrip causes abnormal neocortical development and memory impairments (PMID: 39776340). *SYNCRIP* (also known as *HNRNPQ*) belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family; several genes of this family (including *HNRNPC*, *HNRNPD*, *HNRNPH1*, *HNRNPH2*, *HNRNPK*, *HNRNPR*, and *HNRNPU*) have been recently implicated in neurodevelopmental disorders with overlapping clinical features. In summary, there is definitive evidence supporting the relationship between *SYNCRIP* and autosomal dominant SYNCRIP-related neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 1, 2025 (SOP Version 11).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYNCRIP variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 59

not providedTotal: 57

SYNCRIP-related disorderTotal: 10

SYNCRIP-related neurodevelopmental disorderTotal: 6

not specifiedTotal: 5

Autism spectrum disorderTotal: 2

Neurodevelopmental disorderTotal: 1

SYNCRIP-related Intellectual DisabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006372.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	7 clinvar		10
missense			103 clinvar	4 clinvar	1 clinvar	108
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift	2 clinvar	2 clinvar	8 clinvar			12
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	3	2	119	11	1	136

Highest pathogenic variant AF is 6.8417705e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006372.5	RefSeq	NP_006363.4	10	MANE Select
ENST00000369622.8	Ensembl	ENSP00000358635.3	10	MANE Select
NM_001159673.2	RefSeq	NP_001153145.1	9	Standard
NM_001159674.2	RefSeq	NP_001153146.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mRNA splicing, via spliceosome
osteoblast differentiation
RNA processing
RNA splicing
viral process

Molecular Function

RNA binding
mRNA binding
protein binding
poly(A) binding
mRNA 5'-UTR binding

Cellular Component

nucleus
nucleoplasm
endoplasmic reticulum
membrane
CRD-mediated mRNA stability complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369622
Coding exons: 10
Length: 35458
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125745
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.54	163	349	0.467	0.0000188	4066
Missense (PolyPhen)		29	118.97	0.24375		1563
Synonymous	-0.886	128	116	1.10	0.00000620	1182
Loss of Function	4.75	2	30.1	0.0663	0.00000158	389

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Heterogenous nuclear ribonucleoprotein (hnRNP) implicated in mRNA processing mechanisms. Component of the CRD- mediated complex that promotes MYC mRNA stability. Isoform 1, isoform 2 and isoform 3 are associated in vitro with pre-mRNA, splicing intermediates and mature mRNA protein complexes. Isoform 1 binds to apoB mRNA AU-rich sequences. Isoform 1 is part of the APOB mRNA editosome complex and may modulate the postranscriptional C to U RNA-editing of the APOB mRNA through either by binding to A1CF (APOBEC1 complementation factor), to APOBEC1 or to RNA itself. May be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Interacts in vitro preferentially with poly(A) and poly(U) RNA sequences. Isoform 3 may be involved in cytoplasmic vesicle-based mRNA transport through interaction with synaptotagmins. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma- induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation; seems not to be essential for GAIT complex function. {ECO:0000269|PubMed:11051545, ECO:0000269|PubMed:11134005, ECO:0000269|PubMed:11352648, ECO:0000269|PubMed:11574476, ECO:0000269|PubMed:19029303, ECO:0000269|PubMed:23071094}.;

Recessive Scores

pRec: 0.250

Intolerance Scores

RVIS EVS: -0.56
RVIS percentile EVS: 19.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium