Is IGF2 p.Arg135Ser (c.403C>A) pathogenic?

IGF2 p.Arg135Ser (c.403C>A) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.2597); No allele count reported in gnomAD v4.1 (AN 1,605,384).

How common is IGF2 p.Arg135Ser (c.403C>A) in the general population?

IGF2 p.Arg135Ser (c.403C>A) is no allele count reported in gnomAD v4.1 (AN 1,605,384) (gnomAD).

What do computational predictors say about IGF2 p.Arg135Ser (c.403C>A)?

AlphaMissense predicts likely benign (score 0.2597) — an in-silico prediction, not a clinical call.

IGF2 p.Arg135Ser

c.403C>A · VCV3776738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2597 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,605,384)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2597	likely benign
REVEL	0.394	indeterminate
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP -0.34, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,605,384). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: IGF2
Protein: p.Arg135Ser
Coding: c.403C>A
MANE Select: NM_000612
Type: single nucleotide variant
Location: chr11:2133127 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 135: a UniProt-annotated variant site (in srs3)

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

Similar variants

IGF2 p.Arg135Cys Uncertain significance ★ ⚠ same residue
IGF2 p.Arg135His Uncertain significance ★ ⚠ same residue
INS-IGF2 p.Tyr135Ser Uncertain significance ★ same residue
IGF2 c.157+5G>A Pathogenic ★★ same type
IGF2 p.Glu36Ter Pathogenic/Likely pathogenic ★★ same type
IGF2 p.Gly34Cys Likely pathogenic ★★ same type
IGF2 p.Ser20Ter Likely pathogenic ★★ same type
IGF2 p.Ala167Ser Uncertain significance ★★ ⚠ same type

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-arg135ser (accessed [today's date]).

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