Is IGF2 p.Ser8Ter (c.23C>A) pathogenic?

IGF2 p.Ser8Ter (c.23C>A) is classified Pathogenic in IGF2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-07-23). Absent from gnomAD v4.1; Associated with Silver-Russell syndrome 3.

What condition is associated with IGF2 p.Ser8Ter (c.23C>A)?

IGF2 p.Ser8Ter (c.23C>A) is associated with Silver-Russell syndrome 3 (ClinVar).

How common is IGF2 p.Ser8Ter (c.23C>A) in the general population?

IGF2 p.Ser8Ter (c.23C>A) is absent from gnomAD v4.1 (gnomAD).

How is Silver-Russell syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

IGF2 p.Ser8Ter

c.23C>A · rs869320620 · VCV204491

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Silver-Russell syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP -1.8, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IGF2
Protein: p.Ser8Ter
Coding: c.23C>A
MANE Select: NM_000612
dbSNP: rs869320620
Type: single nucleotide variant
Location: chr11:2135501 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB

Full IGF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Silver-Russell syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Silver-Russell syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

IGF2 p.Ser8= Likely benign ★ same residue
IGF2 p.Gly34Cys Likely pathogenic ★★ same condition
IGF2 p.Ser20Ter Likely pathogenic ★★ same condition
IGF2 p.Arg138Trp Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg156Cys Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly2Glu Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly35Arg Uncertain significance ★★ ⚠ same condition
IGF2 p.Met1Val Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/igf2-p-ser8ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown