Is IGF2 p.Met1Val (c.1A>G) pathogenic?

IGF2 p.Met1Val (c.1A>G) is classified Uncertain significance in IGF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). Very rare (popmax 0.00102%, nfe); Associated with Silver-Russell syndrome 3.

What condition is associated with IGF2 p.Met1Val (c.1A>G)?

IGF2 p.Met1Val (c.1A>G) is associated with Silver-Russell syndrome 3 (ClinVar).

How common is IGF2 p.Met1Val (c.1A>G) in the general population?

IGF2 p.Met1Val (c.1A>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Silver-Russell syndrome inherited?

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

IGF2 p.Met1Val

c.1A>G · VCV3376575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

Silver-Russell syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a LoF-intolerant gene
REVEL	0.27	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.001, phastCons 1
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,478 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.00093% 15/1,612,880 alleles · very rare exomes 15/1,460,610 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)grpmax	0.00102%	98,290

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000612
Type: single nucleotide variant
Location: chr11:2135523 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB

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.Met1Thr Uncertain significance ★★ 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
IGF2 p.Gly2Glu Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly35Arg 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-met1val (accessed [today's date]).

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