AFF4

Chr 5AD

ALF transcription elongation factor 4

ENSG00000072364 UniProt: Q9UHB7 OMIM: 604417

AFF4 encodes a key component of the super elongation complex that increases RNA polymerase II transcription efficiency by suppressing polymerase pausing along DNA. Mutations cause CHOPS syndrome, a multisystem disorder with cognitive disability, colobomas, heart defects, obesity, pulmonary involvement, short stature, and skeletal abnormalities. The condition follows autosomal dominant inheritance and AFF4 is highly constrained against loss-of-function variants, indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.141 OMIM phenotype

Clinical Summary— AFF4

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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.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.14LOEUF

pLI 1.000

Z-score 6.58

OE 0.05 (0.02–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

2.47Z-score

OE missense 0.72 (0.67–0.78)

450 obs / 623.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.14)

0≤0.351.4

Missense OE0.72 (0.67–0.78)

0≤0.61.4

Synonymous OE0.90

0≤1.21.6

LoF obs/exp: 3 / 56.3Missense obs/exp: 450 / 623.9Syn Z: 1.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveAFF4-related Cornelia de Lange-like syndromeGOFAD

0.16100th %ile

GOF

0.14100th %ile

LOF

0.91top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.14

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFGermline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.PMID:25730767

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.