Is IGF2R p.Pro229Ser (c.685C>T) pathogenic?

IGF2R p.Pro229Ser (c.685C>T) is classified Uncertain significance in IGF2R (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1086); Ultra-rare (popmax 0.0164%, mid).

How common is IGF2R p.Pro229Ser (c.685C>T) in the general population?

IGF2R p.Pro229Ser (c.685C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about IGF2R p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

IGF2R p.Pro229Ser

c.685C>T · VCV4274099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -9.69	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 5.8	GERP 0.62, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 79 kb · p 0.39 · regional, not allelic
Overall
CADD	21.5	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,748 alleles · ultra-rare exomes 3/1,461,524 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
South Asian	0.0022%	45,541
European (non-Finnish)	8.48e-05%	1,179,746

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_000876
Type: single nucleotide variant
Location: chr6:160027223 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.48 · 24 PDB
Residue 229: the mrh 2 domain

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

Similar variants

IGF2R p.Pro229Arg Uncertain significance ★ ⚠ same residue
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

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-pro229ser (accessed [today's date]).

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