GFRAL

Chr 6

GDNF family receptor alpha like

Also known as: C6orf144, GRAL, UNQ9356, bA360D14.1

NCBI Gene: 389400ENSG00000187871UniProt: Q6UXV0

Enables glial cell-derived neurotrophic factor receptor activity and receptor tyrosine kinase binding activity. Involved in GDF15-GFRAL signaling pathway; positive regulation of MAPK cascade; and positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction. Located in several cellular components, including actin cytoskeleton; focal adhesion; and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

80
ClinVar variants
9
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GFRAL
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 64 VUS of 80 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.26LOEUF
pLI 0.000
Z-score 0.70
OE 0.83 (0.56–1.26)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.63Z-score
OE missense 1.12 (1.01–1.25)
230 obs / 204.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.83 (0.56–1.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.12 (1.01–1.25)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 16 / 19.3Missense obs/exp: 230 / 204.6Syn Z: 0.05

ClinVar Variant Classifications

80 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic2
VUS64
Likely Benign6
Benign1
7
Pathogenic
2
Likely Pathogenic
64
VUS
6
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
0
0
2
0
2
VUS
0
61
3
0
64
Likely Benign
0
4
2
0
6
Benign
0
0
0
1
1
Total06514180

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GFRAL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist.
Benichou O et al.·Cell Metab
2023Functional
The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.
Emmerson PJ et al.·Nat Med
2017
GDF15: from biomarker to target in cancer cachexia.
Hüllwegen M et al.·Trends Cancer
2025Review
GDF15 mediates the effects of metformin on body weight and energy balance.
Coll AP et al.·Nature
2020
Ectopic expression of GDF15 in cancer-associated fibroblasts enhances melanoma immunosuppression via the GFRAL/RET cascade.
Zhao Z et al.·J Immunother Cancer
2025
GFRAL-Fc disarms GDF15 to reprogram tumor immunity and amplify PD-1 efficacy in hepatocellular carcinoma.
Shi G et al.·Cell Commun Signal
2025
Growth differentiation factor 15: Emerging role in liver diseases.
Li Y et al.·Cytokine
2024Review
GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process.
Salminen A·Biogerontology
2024Review
Targeting the GDF15 Signalling for Obesity Treatment: Recent Advances and Emerging Challenges.
Zhang J et al.·J Cell Mol Med
2024Review
GDF15: An emerging disease target and biomarker of metabolic diseases.
Yang C et al.·J Endocrinol Invest
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools