Is IGF2 p.His168Pro (c.503A>C) pathogenic?

IGF2 p.His168Pro (c.503A>C) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-30). AlphaMissense: likely benign (0.0669); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IGF2 p.His168Pro (c.503A>C)?

IGF2 p.His168Pro (c.503A>C) is associated with Inborn genetic diseases (ClinVar).

How common is IGF2 p.His168Pro (c.503A>C) in the general population?

IGF2 p.His168Pro (c.503A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IGF2 p.His168Pro (c.503A>C)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

IGF2 p.His168Pro

c.503A>C · rs2133582307 · VCV2359297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.85, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	20.3	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: IGF2
Protein: p.His168Pro
Coding: c.503A>C
MANE Select: NM_000612
dbSNP: rs2133582307
Type: single nucleotide variant
Location: chr11:2133027 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 168: a UniProt-annotated variant site (in srs3); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INS-IGF2 p.Gln168Arg Uncertain significance ★ same residue
IGF2 p.His168= Likely benign ★ same residue
IGF2 p.Ala167Ser Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg154Cys Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg156Cys Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg64His Uncertain significance ★★ ⚠ same condition
IGF2 p.Asp165Glu Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly139Val 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-his168pro (accessed [today's date]).

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