Is IGF2 p.Ala167Ser (c.499G>T) pathogenic?

IGF2 p.Ala167Ser (c.499G>T) is classified Uncertain significance in IGF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0732); Very rare (popmax 0.00195%, amr); Associated with Inborn genetic diseases.

What condition is associated with IGF2 p.Ala167Ser (c.499G>T)?

IGF2 p.Ala167Ser (c.499G>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGF2 p.Ala167Ser (c.499G>T) in the general population?

IGF2 p.Ala167Ser (c.499G>T) is very rare (popmax 0.00195%, amr) (gnomAD).

What do computational predictors say about IGF2 p.Ala167Ser (c.499G>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

IGF2 p.Ala167Ser

c.499G>T · rs377316111 · VCV2223330

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -1.7, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 600 bp · p 0.33 · regional, not allelic
Overall
CADD	1.439	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 0.00195% Admixed American · 1/51,380 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000448% 7/1,563,748 alleles · very rare exomes 5/1,411,714 · genomes 2/152,034 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00195%	51,380
European (non-Finnish)	0.00052%	192,411

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.Ala167Ser
Coding: c.499G>T
MANE Select: NM_000612
dbSNP: rs377316111
Type: single nucleotide variant
Location: chr11:2133031 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.96 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 16 PDB
Residue 167: a UniProt-annotated variant site (in srs3); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGF2 p.Ala167Thr Uncertain significance ★ ⚠ same residue
IGF2 p.Arg154Cys Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg156Cys Uncertain significance ★★ ⚠ same condition
IGF2 p.Arg64His Uncertain significance ★★ ⚠ same condition
IGF2 p.Asp165Glu Uncertain significance ★★ ⚠ same condition
IGF2 p.Gly139Val Uncertain significance ★★ ⚠ same condition
IGF2 p.Met1Thr Uncertain significance ★★ same condition
IGF2 p.Thr82Met 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-ala167ser (accessed [today's date]).

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