AFF2

Chr XXLR

ALF transcription elongation factor 2

Also known as: FMR2, FMR2P, FRAXE, MRX2, OX19, XLID109

NCBI Gene: 2334ENSG00000155966UniProt: P51816

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 109MIM #309548
XLR
443
ClinVar variants
95
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— AFF2
🧬
Gene-Disease Validity (ClinGen)
non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
95 Pathogenic / Likely Pathogenic· 265 VUS of 443 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.28LOEUF
pLI 0.996
Z-score 4.98
OE 0.13 (0.07–0.28)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.41Z-score
OE missense 0.82 (0.76–0.89)
413 obs / 502.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.07–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.76–0.89)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 5 / 38.2Missense obs/exp: 413 / 502.0Syn Z: -1.05

ClinVar Variant Classifications

443 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic81
Likely Pathogenic14
VUS265
Likely Benign73
Benign6
Conflicting4
81
Pathogenic
14
Likely Pathogenic
265
VUS
73
Likely Benign
6
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
78
0
81
Likely Pathogenic
5
3
6
0
14
VUS
3
230
30
2
265
Likely Benign
0
35
6
32
73
Benign
0
1
2
3
6
Conflicting
—4
Total1027012237443

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AFF2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AFF2-related fragile X-E intellectual developmental disorder

definitive
Monoallelic X HemizygousUndeterminedAbsent Gene Product
Dev. Disorders
G2P ↗
frameshift variantmissense variant5 prime UTR variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked 109

MIM #309548

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity.
Rooper LM et al.·Am J Surg Pathol
2021
DEK::AFF2 Fusion Carcinomas of Head and Neck.
Ruangritchankul K et al.·Adv Anat Pathol
2023Review
Sinonasal Squamous Cell Carcinoma with DEK::AFF2 Rearrangement : An Aggressive Cancer with Bland Morphology.
Trinquet A et al.·Am J Surg Pathol
2024
DEK :: AFF2 Fusion Sinonasal and Skull Base Nonkeratinizing Squamous Cell Carcinoma : A Clinical Outcome Study Compared With Conventional Sinonasal Squamous Cell Carcinoma.
Hart SA et al.·Am J Surg Pathol
2025
DEK::AFF2 Fusion-Associated Squamous Cell Carcinoma: A Case Series with Literature Review on an Emerging and Challenging Entity.
Amin SE et al.·Head Neck Pathol
2024Review
Translocations and Gene Fusions in Sinonasal Malignancies.
Larkin R et al.·Curr Oncol Rep
2023Review
DEK::AFF2 rearranged neoplasm with undifferentiated morphology and neuroendocrine phenotype in a pediatric patient.
Rullo E et al.·Virchows Arch
2025Case report
Expanding the spectrum of AFF2 carcinoma: clinical, morphological, immunohistochemical, and molecular characteristics of five cases harboring alternate fusions.
Breimer GE et al.·Virchows Arch
2026Case report
DEK::AFF2-Associated Papillary Squamous Cell Carcinoma of the Sinonasal Tract: Clinicopathologic Characterization of 9 Cases.
Zhao Y et al.·Head Neck Pathol
2025Cohort
Sinonasal Adenosquamous Carcinoma - Morphology and Genetic Drivers Including Low- and High-Risk Human Papillomavirus mRNA, DEK::AFF2 Fusion, and MAML2 Rearrangement.
Holliday D Jr et al.·Head Neck Pathol
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Pediatric lacrimal sac non-keratinizing squamous cell carcinoma with DEK-AFF2 gene fusion: clinical and histopathological case report.
Alnahdi MA et al.·Orbit
2025Case report
Expanding the spectrum of AFF2 undifferentiated sarcoma associated to endometriosis: a novel ZDHHC9::AFF2 fusion sarcoma with high-grade features and poor prognosis.
Arciuolo D et al.·Pathologica
2025🔓 Open Access
Aerogenous Dissemination of DEK::AFF2 Carcinoma : A Prototype of a Previously Underrecognized Pattern of Endobronchial Metastasis From Extrathoracic Malignancies.
Sasaki E et al.·Am J Surg Pathol
2026
Novel BMPR1B::AFF2 in a Sinonasal Region Non-Keratinizing Squamous Cell Carcinoma.
Selkin TR et al.·Head Neck Pathol
2025
Resistance mechanism to pembrolizumab in DEK-AFF2 fusion-associated sinonasal squamous cell carcinoma.
Boku S et al.·Int Cancer Conf J
2025Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools