Is IGF2 p.Val67Ile (c.199G>A) pathogenic?

IGF2 p.Val67Ile (c.199G>A) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-12). AlphaMissense: ambiguous (0.4862); Very rare (popmax 0.000169%, nfe); Associated with Silver-Russell syndrome 3.

What condition is associated with IGF2 p.Val67Ile (c.199G>A)?

IGF2 p.Val67Ile (c.199G>A) is associated with Silver-Russell syndrome 3 (ClinVar).

How common is IGF2 p.Val67Ile (c.199G>A) in the general population?

IGF2 p.Val67Ile (c.199G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Silver-Russell syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about IGF2 p.Val67Ile (c.199G>A)?

AlphaMissense predicts ambiguous (score 0.4862) — an in-silico prediction, not a clinical call.

IGF2 p.Val67Ile

c.199G>A · rs1564894953 · VCV1328522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Silver-Russell syndrome 3

Computational evidence

Protein change
AlphaMissense	0.4862	ambiguous
REVEL	0.711	pathogenic-leaning
SaProt	LLR -10.62	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 1,851 bp · p 3.2e-08 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,054 alleles · very rare exomes 3/1,460,734 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,492
European (non-Finnish)grpmax	0.000169%	589,998

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.Val67Ile
Coding: c.199G>A
MANE Select: NM_000612
dbSNP: rs1564894953
Type: single nucleotide variant
Location: chr11:2133624 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 67: a UniProt-annotated variant site (in srs3); an α-helix; the 'a' region

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

Disease context

Silver-Russell syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Silver-Russell syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

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
IGF2 p.Gly2Glu Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly35Arg Uncertain significance ★★ ⚠ same condition
IGF2 p.Met1Val Uncertain significance ★★ same condition
IGF2 p.Met5Val 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-val67ile (accessed [today's date]).

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