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DDG2P

Gene: FRYL

Green List (high evidence)
FRYL (FRY like transcription coactivator)
EnsemblGeneIds (GRCh38): ENSG00000075539
EnsemblGeneIds (GRCh37): ENSG00000075539
FRYL is in 3 panels

3 reviews

Julie Evans (South West Genomic Laboratory Hub)

I don't know

Not sure this gene should be rated green. It has a high number of loss of function variants in gnomAD. Since the gene was upgraded to green LOF variants are being tiered in GMS WGS cases but without sufficient evidence to apply PVS1. The gene is not curated in ClinGen and only has moderate evidence in Gene 2 Phenotype. There is no applicable mouse model. The green rating seems to be based on a single publication (PMID: 38479391).
Created: 28 Aug 2026, 11:39 a.m. | Last Modified: 28 Aug 2026, 11:39 a.m.
Panel Version: 8.1
Created: 28 Aug 2026, 11:39 a.m.
Last Modified: 28 Aug 2026, 11:39 a.m.
Panel version: 8.1

Ida Ertmanska (Genomics England Curator)

Comment on phenotypes: OMIM phenotype added 20 Mar 2026.
Created: 20 Mar 2026, 11:14 a.m. | Last Modified: 20 Mar 2026, 11:14 a.m.
Panel Version: 6.439
Created: 20 Mar 2026, 11:14 a.m.
Last Modified: 20 Mar 2026, 11:14 a.m.
Panel version: 6.439

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is evidence available from only a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated green.

However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/) Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of 'moderate' and above should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.
Created: 2 Sep 2026, 11:21 a.m. | Last Modified: 2 Sep 2026, 11:22 a.m.
Panel Version: 8.2
PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution.

Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support.

Key concerns limiting confidence:
(1) Half of the reported variants (7) are present in gnomAD v4.1.1.
(2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism.
(3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar.
(4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease
(5) No familial segregation data exist (all cases simplex).
(6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution.

This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp.
Created: 2 Sep 2026, 11:09 a.m. | Last Modified: 2 Sep 2026, 11:11 a.m.
Panel Version: 8.1
The DDG2P confidence category, allelic requirement and molecular mechanism for FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities are moderate, monoallelic_autosomal and loss of function (PMID:38479391). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03728.
Created: 13 Feb 2026, 9:26 p.m. | Last Modified: 13 Feb 2026, 9:26 p.m.
Panel Version: 6.17

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities

Publications

Created: 13 Feb 2026, 9:26 p.m.
Last Modified: 2 Sep 2026, 11:22 a.m.
Panel version: 8.1

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • DD-Gene2Phenotype
Phenotypes
  • Pan-Chung-Bellen syndrome, OMIM:621049
  • Pan-Chung-Bellen syndrome, MONDO:0975953
Clinvar variants
Variants in FRYL
Penetrance
None
Publications
Panels with this gene

History Filter Activity

2 Sep 2026, Gel status: 3

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: fryl has been classified as Green List (High Evidence).

20 Mar 2026, Gel status: 3

Removed Tag

Ida Ertmanska (Genomics England Curator)

Tag gene-checked was removed from gene: FRYL.

20 Mar 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: FRYL were changed from Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953

20 Mar 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: FRYL were changed from MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities

19 Mar 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag gene-checked tag was added to gene: FRYL.

13 Feb 2026, Gel status: 3

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

gene: FRYL was added gene: FRYL was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FRYL were set to 38479391 Phenotypes for gene: FRYL were set to MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities