Is IGF2 p.Pro173Ser (c.517C>T) pathogenic?

IGF2 p.Pro173Ser (c.517C>T) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0614); Very rare (popmax 0.000784%, nfe).

How common is IGF2 p.Pro173Ser (c.517C>T) in the general population?

IGF2 p.Pro173Ser (c.517C>T) is very rare (popmax 0.000784%, nfe) (gnomAD).

What do computational predictors say about IGF2 p.Pro173Ser (c.517C>T)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

IGF2 p.Pro173Ser

c.517C>T · rs11545014 · VCV3023243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000784%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.22	GERP -1.4, phastCons 0.002
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	2.008	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 0.000784% European (non-Finnish) · 9/1,148,510 alleles

Filtering AF 0.000369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000645% 10/1,550,686 alleles · very rare exomes 9/1,398,522 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00168%	59,566
European (non-Finnish)grpmax	0.000784%	127,612

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro173Ser
Coding: c.517C>T
MANE Select: NM_000612
dbSNP: rs11545014
Type: single nucleotide variant
Location: chr11:2133013 (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.Pro173= Likely benign ★ same residue
IGF2 p.Pro173fs Uncertain significance ★ same residue
IGF2 c.157+5G>A Pathogenic ★★ same type
IGF2 p.Glu36Ter Pathogenic/Likely pathogenic ★★ same type
IGF2 p.Gly34Cys 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-pro173ser (accessed [today's date]).

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