Is IGF2 p.Cys84Arg (c.250T>C) pathogenic?

IGF2 p.Cys84Arg (c.250T>C) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9923); Absent from gnomAD v4.1; Associated with Silver-Russell syndrome 3.

What condition is associated with IGF2 p.Cys84Arg (c.250T>C)?

IGF2 p.Cys84Arg (c.250T>C) is associated with Silver-Russell syndrome 3 (ClinVar).

How common is IGF2 p.Cys84Arg (c.250T>C) in the general population?

IGF2 p.Cys84Arg (c.250T>C) 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.

What do computational predictors say about IGF2 p.Cys84Arg (c.250T>C)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

IGF2 p.Cys84Arg

c.250T>C · VCV4854315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Silver-Russell syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic · top 4% in IGF2
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -10.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Cys84Arg
Coding: c.250T>C
MANE Select: NM_000612
Type: single nucleotide variant
Location: chr11:2133573 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 84: a disulfide bond; a UniProt-annotated variant site (in srs3); the 'a' region

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.Cys84Trp Likely pathogenic ★ same residue
IGF2 p.Cys84Gly Uncertain significance ★ ⚠ 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

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-cys84arg (accessed [today's date]).

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