Is IGF2 p.Pro173Gln (c.518C>A) pathogenic?

IGF2 p.Pro173Gln (c.518C>A) is classified Uncertain significance in IGF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-20). AlphaMissense: likely benign (0.0719); Very rare (popmax 0.00469%, eas); Associated with Beckwith-Wiedemann syndrome.

What condition is associated with IGF2 p.Pro173Gln (c.518C>A)?

IGF2 p.Pro173Gln (c.518C>A) is associated with Beckwith-Wiedemann syndrome, Wilms tumor 1, Silver-Russell syndrome 3 (ClinVar).

How common is IGF2 p.Pro173Gln (c.518C>A) in the general population?

IGF2 p.Pro173Gln (c.518C>A) is very rare (popmax 0.00469%, eas) (gnomAD).

What do computational predictors say about IGF2 p.Pro173Gln (c.518C>A)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

IGF2 p.Pro173Gln

c.518C>A · VCV3891375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00469%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Beckwith-Wiedemann syndrome

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -6.32	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 3.6	GERP 0.7, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	17.43	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

Grpmax group 0.00469% East Asian · 2/42,614 alleles

Filtering AF 0.000778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000291%

Overall 0.000647% 10/1,545,720 alleles · very rare exomes 8/1,393,674 · genomes 2/152,046 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00469%	21,307
Admixed American	0.00405%	24,672
Finnishnot grpmax-eligible	0.00163%	61,410
African / African-American	0.00138%	72,304
European (non-Finnish)	0.000349%	286,448

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.Pro173Gln
Coding: c.518C>A
MANE Select: NM_000612
Type: single nucleotide variant
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

Disease context

Beckwith-Wiedemann syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wilms tumor 1 Silver-Russell syndrome 3 Silver-Russell syndrome 1

Similar variants

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.Gly34Cys Likely pathogenic ★★ same condition
IGF2 p.Ser20Ter Likely pathogenic ★★ same condition
IGF2 p.Arg138Trp Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg156Cys 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-pro173gln (accessed [today's date]).

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