AFF2

protein-coding

ALF transcription elongation factor 2, the group of AF4/FMR2 family|Super elongation complex

Gene summary

This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]

Previous symbols:

FMR2

MANE transcript

NM_002025.4

Inheritance

ClinVar variants

P:27U:427B:107

Top phenotype

Premature ovarian failure

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chrX:148,500,617-149,000,663

External References & Databases

Ensembl (ENSG00000155966)

Transcript & Mutation Effects

hg38 • Region Span ~500.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic X-linked intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

The *AFF2* gene encodes a protein involved in transcriptional regulation and alternative splicing. *AFF2* was first reported in relation to X-linked non-syndromic intellectual disability in 1996 (Gecz et al., PMID: 8673085). *AFF2*, previously referred to as *FMR2*, is associated with the folate-sensitive fragile X E (FRAXE) locus on chromosome Xq28. FRAXE intellectual disability syndrome can result from the silencing of the *AFF2* gene due to a CCG expansion in the 5' UTR of the gene, or from deletions or loss-of-function variants. Affected males commonly present with developmental delay, mild to moderate intellectual disability, communication deficits, and behavioral abnormalities, including autism or autistic behavior, attention deficit, and hyperactivity. Some individuals may exhibit mild dysmorphic facial features. Carrier females are unaffected. Four variants (the 5' UTR repeat expansion and three intragenic deletions) that have been reported in eight probands in five publications (PMIDs: 7783162, 8023854, 8334699, 21739600, 22065534) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *AFF2* is highly constrained for loss-of-function variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model and functional alterations in patient cells. In summary, there is definitive evidence supporting the relationship between *AFF2* and X-linked non-syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on August 11, 2025 (SOP Version 11). Although new cases were added, the classification did not change.

FRAXE intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010659

Submitter: G2P

FRAXE intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010659

Submitter: Orphanet

FRAXE intellectual disabilitySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010659

Submitter: PanelApp Australia

FRAXE intellectual disabilitySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010659

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Premature ovarian failureXL

Manifestation: Endocrine; Neurologic; Obstetric

Intervention: Obstetric

Rationale: Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency

Refs: 8334699; 8023854; 7536393; 7783162; 8673085; 8651274; 9341861; 9475603; 10528856; 12605436; 19136466; 21739600

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AFF2 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 247

Inborn genetic diseasesTotal: 128

FRAXETotal: 69

not specifiedTotal: 61

AFF2-related disorderTotal: 25

Intellectual disabilityTotal: 4

Non-syndromic X-linked intellectual disabilityTotal: 3

Moderate intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002025.4. 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			28 clinvar	51 clinvar	4 clinvar	83
missense	1 clinvar	3 clinvar	355 clinvar	52 clinvar		411
nonsense	7 clinvar	3 clinvar	21 clinvar			31
start loss						0
frameshift	7 clinvar	2 clinvar				9
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	23 clinvar			27
Total	16	11	427	103	4	561

Highest pathogenic variant AF is 0.000008901469

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002025.4	RefSeq	NP_002016.2	21	MANE Select
ENST00000370460.7	Ensembl	ENSP00000359489.2	21	MANE Select
NM_001169122.2	RefSeq	NP_001162593.1	20	Standard
NM_001169123.2	RefSeq	NP_001162594.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
mRNA processing
brain development
learning or memory
RNA splicing

Molecular Function

G-quadruplex RNA binding
double-stranded DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
transcription elongation factor complex
nuclear speck
ELL-EAF complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370460
Coding exons: 21
Length: 500055
Individuals with no LoFs: 125735
Homozygous LoFs: 4
Heterozygous LoFs: 8
Defined: 125747
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.41	413	502	0.823	0.0000379	8652
Missense (PolyPhen)		183	237.35	0.77103		4184
Synonymous	-1.05	205	187	1.10	0.0000145	2582
Loss of Function	4.98	5	38.2	0.131	0.00000281	689

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.00012	rare
Latino/Admixed American	0.00011	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00014	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000050	0.000035	rare
South Asian	0.000058	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein. Might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure. {ECO:0000269|PubMed:19136466}.;

Recessive Scores

pRec: 0.280

Intolerance Scores

LoFtool: 0.205
RVIS EVS: -1.08
RVIS percentile EVS: 7.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0786

Gene Damage Prediction

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