YTHDF1

Chr 20

YTH N6-methyladenosine RNA binding protein F1

ENSG00000149658 UniProt: Q9BYJ9 OMIM: 616529

YTHDF1 encodes a protein that specifically recognizes and binds N6-methyladenosine (m6A)-containing mRNAs and regulates their stability and translation, playing essential roles in learning, memory formation, and axon guidance in the nervous system. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.24), suggesting that mutations would likely cause severe developmental consequences, though specific disease associations have not yet been established in patients. Given its critical function in neuronal mRNA regulation and memory formation, pathogenic variants would be expected to cause neurodevelopmental disorders.

OMIM ResearchSummary from RefSeq, UniProt

Specifically recognizes and binds N6-methyladenosine (m6A)-containing mRNAs, and regulates their stability (PubMed:24284625, PubMed:26318451, PubMed:32492408, PubMed:39900921). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:24284625, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex (PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) shares m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). Required to facilitate learning and memory formation in the hippocampus by binding to m6A-containing neuronal mRNAs (By similarity). Acts as a regulator of axon guidance by binding to m6A-containing ROBO3 transcripts (By similarity). Acts as a negative regulator of antigen cross-presentation in myeloid dendritic cells (By similarity). In the context of tumorigenesis, negative regulation of antigen cross-presentation limits the anti-tumor response by reducing efficiency of tumor-antigen cross-presentation (By similarity). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31292544, PubMed:31388144, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544)

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.24

Clinical Summary— YTHDF1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.994

Z-score 3.91

OE 0.05 (0.02–0.24)

Highly constrained

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

Missense Constraint?

1.60Z-score

OE missense 0.76 (0.69–0.84)

263 obs / 346.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.24)

0≤0.351.4

Missense OE?0.76 (0.69–0.84)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 1 / 19.7Missense obs/exp: 263 / 346.8Syn Z: -1.09

This gene — mechanism propensity

0.3594th %ile

GOF

0.3887th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

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