Is IGFBP1 p.Arg53Pro (c.158G>C) pathogenic?

IGFBP1 p.Arg53Pro (c.158G>C) is classified Uncertain significance in IGFBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1475); Absent from gnomAD v4.1.

How common is IGFBP1 p.Arg53Pro (c.158G>C) in the general population?

IGFBP1 p.Arg53Pro (c.158G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IGFBP1 p.Arg53Pro (c.158G>C)?

AlphaMissense predicts likely benign (score 0.1475) — an in-silico prediction, not a clinical call.

IGFBP1 p.Arg53Pro

c.158G>C · VCV4678060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1475 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1475	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.42, phastCons 0.024
Regional constraint	o/e 0.97	unconstrained · MANE · 4,435 bp · p 0.62 · regional, not allelic
Overall
CADD	17.1	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

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: IGFBP1
Protein: p.Arg53Pro
Coding: c.158G>C
MANE Select: NM_000596
Type: single nucleotide variant
Location: chr7:45888810 (GRCh38)
Gene constraint: LOEUF 1.856 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB
Residue 53: a disulfide bond; the igfbp n-terminal domain

Full IGFBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFBP1 p.Ala110Asp Uncertain significance ★ ⚠ same type
IGFBP1 p.Ala118Glu Uncertain significance ★ ⚠ same type
IGFBP1 p.Ala55Ser Uncertain significance ★ ⚠ same type
IGFBP1 p.Arg85Cys Uncertain significance ★ ⚠ same type
IGFBP1 p.Asp109Gly Uncertain significance ★ ⚠ same type
IGFBP1 p.Cys41Tyr Uncertain significance ★ ⚠ same type
IGFBP1 p.Cys59Trp Uncertain significance ★ ⚠ same type
IGFBP1 p.Glu125Lys 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/igfbp1-p-arg53pro (accessed [today's date]).

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