Is IGF2 p.Val141Met (c.421G>A) pathogenic?

IGF2 p.Val141Met (c.421G>A) is classified Uncertain significance in IGF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.066); Ultra-rare (popmax 0.0166%, mid); Associated with IGF2-related disorder.

What condition is associated with IGF2 p.Val141Met (c.421G>A)?

IGF2 p.Val141Met (c.421G>A) is associated with IGF2-related disorder (ClinVar).

How common is IGF2 p.Val141Met (c.421G>A) in the general population?

IGF2 p.Val141Met (c.421G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about IGF2 p.Val141Met (c.421G>A)?

AlphaMissense predicts likely benign (score 0.066) — an in-silico prediction, not a clinical call.

IGF2 p.Val141Met

c.421G>A · rs375129654 · VCV2064076

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IGF2-related disorder

Computational evidence

Protein change
AlphaMissense	0.066	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -6.19	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 -4.7	GERP -1.6
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	0.021	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 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00305% 49/1,607,202 alleles · ultra-rare exomes 46/1,454,982 · genomes 3/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
Remaining individualsnot grpmax-eligible	0.00965%	10,359
African / African-American	0.00401%	24,915
Admixed American	0.00338%	29,606
European (non-Finnish)	0.00289%	34,602
East Asian	0.00224%	44,570
Finnishnot grpmax-eligible	0.00158%	63,150
South Asian	0.0011%	90,548

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.Val141Met
Coding: c.421G>A
MANE Select: NM_000612
dbSNP: rs375129654
Type: single nucleotide variant
Location: chr11:2133109 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 141: a UniProt-annotated variant site (in srs3)

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

Disease context

IGF2-related disorder

Similar variants

IGF2 c.157+5G>A Pathogenic ★★ same condition
IGF2 p.Ser20Ter Likely pathogenic ★★ same condition
IGF2 p.Glu174Ala Uncertain significance ⚠ same condition
IGF2 p.Met5Lys Uncertain significance ⚠ same condition
IGF2 p.Pro166Thr Uncertain significance ⚠ same condition
IGF2 p.Val100Met Uncertain significance ⚠ same condition
IGF2 c.-248-73= Benign same condition
IGF2 c.*1958= Benign 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-val141met (accessed [today's date]).

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