Is IGF2R p.Ser2183Pro (c.6547T>C) pathogenic?

IGF2R p.Ser2183Pro (c.6547T>C) is classified Uncertain significance in IGF2R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.1216); Very rare (popmax 0.00112%, sas).

How common is IGF2R p.Ser2183Pro (c.6547T>C) in the general population?

IGF2R p.Ser2183Pro (c.6547T>C) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about IGF2R p.Ser2183Pro (c.6547T>C)?

AlphaMissense predicts likely benign (score 0.1216) — an in-silico prediction, not a clinical call.

IGF2R p.Ser2183Pro

c.6547T>C · rs2483596545 · VCV3108582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1216	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.21	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 1.5	GERP -0.37, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 57 kb · p 3.4e-14 · regional, not allelic
Overall
CADD	19.04	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 0.00112% South Asian · 1/89,464 alleles

Overall 6.22e-05% 1/1,607,116 alleles · very rare exomes 1/1,454,854 · genomes 0/152,262 · joint denominator

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: IGF2R
Protein: p.Ser2183Pro
Coding: c.6547T>C
MANE Select: NM_000876
dbSNP: rs2483596545
Type: single nucleotide variant
Location: chr6:160089995 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.48 · 24 PDB
Residue 2183: the mrh 15 domain

Full IGF2R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGF2R p.Asp2219= Benign/Likely benign ★★ same type
IGF2R p.Leu817Val Benign ★★ same type
IGF2R p.Pro2129= Benign/Likely benign ★★ same type
IGF2R p.His151Tyr Likely pathogenic ★ ⚠ same type
IGF2R c.289+2T>C Uncertain significance ★ same type
IGF2R p.Ala1033Pro Uncertain significance ★ ⚠ same type
IGF2R p.Ala104Thr Uncertain significance ★ ⚠ same type
IGF2R p.Ala1252Thr 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/igf2r-p-ser2183pro (accessed [today's date]).

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