Is IGF2 p.Arg27Cys (c.79C>T) pathogenic?

IGF2 p.Arg27Cys (c.79C>T) is classified Uncertain significance in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). AlphaMissense: likely benign (0.3254); Very rare (popmax 0.0011%, sas).

How common is IGF2 p.Arg27Cys (c.79C>T) in the general population?

IGF2 p.Arg27Cys (c.79C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about IGF2 p.Arg27Cys (c.79C>T)?

AlphaMissense predicts likely benign (score 0.3254) — an in-silico prediction, not a clinical call.

IGF2 p.Arg27Cys

c.79C>T · rs1230176657 · VCV2856101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3254	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -14.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 80 bp · p 0.47 · regional, not allelic
Overall
CADD	29.8	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 0.0011% South Asian · 1/91,084 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,676 alleles · very rare exomes 9/1,461,454 · genomes 4/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.00102%	98,333

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.Arg27Cys
Coding: c.79C>T
MANE Select: NM_000612
dbSNP: rs1230176657
Type: single nucleotide variant
Location: chr11:2135445 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 27: a UniProt-annotated variant site (in srs3); the 'b' region

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

Similar variants

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
IGF2 p.Arg156Cys 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-arg27cys (accessed [today's date]).

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