GFRA2

Chr 8

GDNF family receptor alpha 2

Also known as: GDNFRB, NRTNR-ALPHA, NTNRA, RETL2, TRNR2

NCBI Gene: 2675 ENSG00000168546 UniProt: O00451 OMIM: 601956

The protein is a GPI-linked cell surface receptor that binds neurturin and GDNF to activate the RET tyrosine kinase receptor, supporting survival of sympathetic neurons. GFRA2 mutations cause congenital central hypoventilation syndrome and Hirschsprung disease through autosomal dominant inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.69), and these conditions affect the autonomic nervous system with onset in the neonatal period.

OMIM ResearchSummary from RefSeq, UniProt

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.098

Z-score 2.36

OE 0.30 (0.15–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.14Z-score

OE missense 0.97 (0.86–1.10)

191 obs / 196.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.15–0.69)

0≤0.351.4

Missense OE?0.97 (0.86–1.10)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 4 / 13.3Missense obs/exp: 191 / 196.6Syn Z: -1.44

Background carrier burden — how many people carry a rare variant somewhere in GFRA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

705 rare PASS variants

Rare truncating (LoF)

1 in 6,000

37 rare PASS variants

Rare synonymous (reference)

1 in 160

321 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GFRA2. 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 150	1 in 8,700
South Asian	~43k	1 in 80	1 in 6,900
Remaining (unassigned)	~30k	1 in 84	1 in 3,300
European (Finnish)	~27k	1 in 460	≈ 1 in 27,000
Admixed American	~22k	1 in 62	1 in 3,000
African / African American	~21k	1 in 65	1 in 820
East Asian	~20k	1 in 74	≈ 1 in 19,000
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 95	≈ 1 in 2,900

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): 8 of 9 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 9.? see exons ↓