IGF2

Chr 11AD

insulin like growth factor 2

Also known as: C11orf43, GRDF, IGF-II, PP9974, SRS3

NCBI Gene: 3481 ENSG00000167244 UniProt: P01344 OMIM: 147470

The protein encoded by this gene is insulin-like growth factor 2, a major fetal growth hormone that regulates fetoplacental development and tissue differentiation, and in adults is involved in glucose metabolism in adipose tissue, skeletal muscle and liver. Mutations cause Silver-Russell syndrome 3, characterized by growth restriction, with autosomal dominant inheritance. This is an imprinted gene expressed only from the paternal allele, and the gene shows tolerance to loss-of-function variants (pLI 0.04).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.131 OMIM phenotype

Clinical Summary— IGF2

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Gene-Disease Validity (ClinGen)

Silver-Russell syndrome 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 112 VUS of 209 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — IGF2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.13LOEUF

pLI 0.044

Z-score 1.36

OE 0.44 (0.20–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.93Z-score

OE missense 0.79 (0.69–0.92)

127 obs / 160.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.20–1.13)

0≤0.351.4

Missense OE?0.79 (0.69–0.92)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 3 / 6.8Missense obs/exp: 127 / 160.2Syn Z: -0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveIGF2-related Silver-Russell syndromeLOFAD

definitiveIGF2-related Beckwith-Wiedemann syndromeGOFAD

This gene — mechanism propensity

0.73top 25%

GOF

0.4972th %ile

LOF

0.3453th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThese mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 28873464 ↗

ClinVar Variant Classifications

209 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic11

VUS112

Likely Benign54

Benign8

Conflicting10

Pathogenic

Likely Pathogenic

112

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	2	2	0	14
Likely Pathogenic	8	3	0	0	11
VUS	8	97	6	1	112
Likely Benign	0	7	5	42	54
Benign	0	0	4	4	8
Conflicting	—				10
Total	26	109	17	47	209

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap IGF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →