FRRS1L

Chr 9

ferric chelate reductase 1 like

Also known as: C9orf4, CG-6, CG6, DEE37, EIEE37

NCBI Gene: 23732 ENSG00000260230 UniProt: Q9P0K9

The protein is a component of the outer core of AMPA receptors in the brain that modulates glutamate signaling. Biallelic mutations cause developmental and epileptic encephalopathy 37, inherited in an autosomal recessive pattern. The pathogenic mechanism involves disrupted glutamate receptor function leading to abnormal neuronal excitability and seizures.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Mutations in this gene are associated with early infantile epileptic encephalopathy 37. [provided by RefSeq, Jul 2016]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 37

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · genetic developmental and epileptic encephalopathy · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.09

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.09LOEUF

pLI 0.001

Z-score 1.37

OE 0.55 (0.30–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.58Z-score

OE missense 0.86 (0.74–1.00)

121 obs / 140.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.30–1.09)

0≤0.351.4

Missense OE?0.86 (0.74–1.00)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 6 / 10.9Missense obs/exp: 121 / 140.4Syn Z: -0.03

Background carrier burden — how many people carry a rare variant somewhere in FRRS1L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

419 rare PASS variants

Rare truncating (LoF)

1 in 2,200

54 rare PASS variants

Rare synonymous (reference)

1 in 230

172 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FRRS1L. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 300	1 in 2,000
South Asian	~43k	1 in 160	1 in 2,500
Remaining (unassigned)	~30k	1 in 120	1 in 3,600
European (Finnish)	~27k	1 in 800	≈ 1 in 6,200
Admixed American	~22k	1 in 130	1 in 2,100
African / African American	~21k	1 in 100	1 in 2,600
East Asian	~20k	1 in 130	1 in 3,000
Ashkenazi Jewish	~13k	1 in 1,400	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 5 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 4 of 5 (exon 1 below).? see exons ↓