Is IGF2 p.Pro98Leu (c.293C>T) pathogenic?

IGF2 p.Pro98Leu (c.293C>T) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-03). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.00401%, afr).

How common is IGF2 p.Pro98Leu (c.293C>T) in the general population?

IGF2 p.Pro98Leu (c.293C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about IGF2 p.Pro98Leu (c.293C>T)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

IGF2 p.Pro98Leu

c.293C>T · rs143785521 · VCV2896604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -7.16	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 1.9	GERP -1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	19.64	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 0.00401% African / African-American · 3/74,872 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00136% 22/1,611,814 alleles · very rare exomes 19/1,459,614 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,957
Remaining individualsnot grpmax-eligible	0.0032%	31,208
Admixed American	0.00167%	59,904
Finnishnot grpmax-eligible	0.00159%	63,050
European (non-Finnish)	0.00127%	78,628

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.Pro98Leu
Coding: c.293C>T
MANE Select: NM_000612
dbSNP: rs143785521
Type: single nucleotide variant
Location: chr11:2133530 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 98: a UniProt-annotated variant site (in srs3)

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

Similar variants

INS-IGF2 p.Ala98Pro 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
IGF2 p.Ser20Ter Likely pathogenic ★★ same type
IGF2 p.Ala167Ser Uncertain significance ★★ ⚠ same type
IGF2 p.Arg138Trp Uncertain significance ★★ ⚠ same type
IGF2 p.Arg154Cys Uncertain significance ★★ ⚠ 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-pro98leu (accessed [today's date]).

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