Is IGF2 p.Pro173fs (c.518del) pathogenic?

IGF2 p.Pro173fs (c.518del) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). Very rare (popmax 0.00609%, amr).

How common is IGF2 p.Pro173fs (c.518del) in the general population?

IGF2 p.Pro173fs (c.518del) is very rare (popmax 0.00609%, amr) (gnomAD).

IGF2 p.Pro173fs

c.518del · VCV3372485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00609%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.9	GERP -1.4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00609% Admixed American · 3/49,284 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000848%

Overall 0.00103% 16/1,545,910 alleles · very rare exomes 16/1,394,088 · genomes 0/151,822 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00609%	16,428
Ashkenazi Jewishnot grpmax-eligible	0.00382%	26,178
East Asian	0.00235%	42,564
African / African-American	0.00138%	72,296
European (non-Finnish)	0.000873%	114,612

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: IGF2
Protein: p.Pro173fs
Coding: c.518del
MANE Select: NM_000612
Type: Deletion
Location: chr11:2133012 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 173: a UniProt-annotated variant site (in srs3); a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

IGF2 p.Pro173Gln Uncertain significance ★★ ⚠ same residue
IGF2 p.Pro173Arg Uncertain significance ★ ⚠ same residue
IGF2 p.Pro173Leu Uncertain significance ★ ⚠ same residue
IGF2 p.Pro173Ser Uncertain significance ★ ⚠ same residue
IGF2 p.Pro173= Likely benign ★ same residue
IGF2 p.Pro157_Leu158insTer Uncertain significance ★★ same type
IGF2 p.Arg61_Arg62insTer Likely pathogenic ★ same type
IGF2 p.Asp76fs Likely pathogenic ★ 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-pro173fs (accessed [today's date]).

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