Is IGF2 p.Phe50Cys (c.149T>G) pathogenic?

IGF2 p.Phe50Cys (c.149T>G) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.995); Absent from gnomAD v4.1.

How common is IGF2 p.Phe50Cys (c.149T>G) in the general population?

IGF2 p.Phe50Cys (c.149T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IGF2 p.Phe50Cys (c.149T>G)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

IGF2 p.Phe50Cys

c.149T>G · VCV4528161

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 3% in IGF2
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -14.47	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 1,851 bp · p 3.2e-08 · regional, not allelic
Overall
CADD	33.0	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.Phe50Cys
Coding: c.149T>G
MANE Select: NM_000612
Type: single nucleotide variant
Location: chr11:2135375 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 50: a UniProt-annotated variant site (in srs3); a β-strand; the 'b' region

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

Similar variants

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
IGF2 p.Arg138Trp Uncertain significance ★★ ⚠ same type
IGF2 p.Arg154Cys Uncertain significance ★★ ⚠ same type
IGF2 p.Arg156Cys 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-phe50cys (accessed [today's date]).

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