Is IGF2 p.Pro173Leu (c.518C>T) pathogenic?

IGF2 p.Pro173Leu (c.518C>T) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely benign (0.0713); Very rare (popmax 0.00415%, afr); Associated with Inborn genetic diseases.

What condition is associated with IGF2 p.Pro173Leu (c.518C>T)?

IGF2 p.Pro173Leu (c.518C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGF2 p.Pro173Leu (c.518C>T) in the general population?

IGF2 p.Pro173Leu (c.518C>T) is very rare (popmax 0.00415%, afr) (gnomAD).

What do computational predictors say about IGF2 p.Pro173Leu (c.518C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

IGF2 p.Pro173Leu

c.518C>T · rs1050342 · VCV2324468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.18	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 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	15.37	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 0.00415% African / African-American · 3/72,304 alleles

Filtering AF 0.0011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000505%

Overall 0.000388% 6/1,545,720 alleles · very rare exomes 3/1,393,674 · genomes 3/152,046 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00415%	24,101
European (non-Finnish)	0.000262%	381,932

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.Pro173Leu
Coding: c.518C>T
MANE Select: NM_000612
dbSNP: rs1050342
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

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

Similar variants

IGF2 p.Pro173Gln Uncertain significance ★★ ⚠ same residue
IGF2 p.Pro173Arg Uncertain significance ★ ⚠ same residue
IGF2 p.Pro173Ser Uncertain significance ★ ⚠ same residue
IGF2 p.Pro173= 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

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-pro173leu (accessed [today's date]).

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