Is IGF2BP3 p.Pro28Arg (c.83C>G) pathogenic?

IGF2BP3 p.Pro28Arg (c.83C>G) is classified Uncertain significance in IGF2BP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.4398); Very rare (popmax 0.000339%, nfe).

How common is IGF2BP3 p.Pro28Arg (c.83C>G) in the general population?

IGF2BP3 p.Pro28Arg (c.83C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about IGF2BP3 p.Pro28Arg (c.83C>G)?

AlphaMissense predicts ambiguous (score 0.4398) — an in-silico prediction, not a clinical call.

IGF2BP3 p.Pro28Arg

c.83C>G · VCV4678020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4398	ambiguous
REVEL	0.312	indeterminate
SaProt	LLR -10.71	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP -0.37, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 119 kb · p 0.85 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,758 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,770 alleles · very rare exomes 2/1,460,574 · genomes 2/152,196 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IGF2BP3
Protein: p.Pro28Arg
Coding: c.83C>G
MANE Select: NM_006547
Type: single nucleotide variant
Location: chr7:23470028 (GRCh38)
Gene constraint: LOEUF 0.196 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.71 · 5 PDB
Residue 28: the rrm 1 domain

Full IGF2BP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGF2BP3 p.Pro28Ala Uncertain significance ★ ⚠ same residue
IGF2BP3 p.Ala14Asp Uncertain significance ★ ⚠ same type
IGF2BP3 p.Ala237Val Uncertain significance ★ ⚠ same type
IGF2BP3 p.Ala239Ser Uncertain significance ★ ⚠ same type
IGF2BP3 p.Ala392Thr Uncertain significance ★ ⚠ same type
IGF2BP3 p.Arg171His Uncertain significance ★ ⚠ same type
IGF2BP3 p.Arg199His Uncertain significance ★ ⚠ same type
IGF2BP3 p.Arg219Gln 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/igf2bp3-p-pro28arg (accessed [today's date]).

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