Is IGFBP5 p.Pro232Ser (c.694C>T) pathogenic?

IGFBP5 p.Pro232Ser (c.694C>T) is classified Uncertain significance in IGFBP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.9702); Very rare (popmax 0.00223%, eas).

How common is IGFBP5 p.Pro232Ser (c.694C>T) in the general population?

IGFBP5 p.Pro232Ser (c.694C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about IGFBP5 p.Pro232Ser (c.694C>T)?

AlphaMissense predicts likely pathogenic (score 0.9702) — an in-silico prediction, not a clinical call.

IGFBP5 p.Pro232Ser

c.694C>T · VCV4274157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9702	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 18 kb · p 0.16 · regional, not allelic
Overall
CADD	29.3	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 0.00223% East Asian · 1/44,876 alleles

Overall 6.84e-05% 1/1,461,780 alleles · very rare

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: IGFBP5
Protein: p.Pro232Ser
Coding: c.694C>T
MANE Select: NM_000599
Type: single nucleotide variant
Location: chr2:216676876 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.91 · 3 PDB
Residue 232: a disulfide bond; the thyroglobulin type-1 domain

Full IGFBP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFBP5 p.Ala180Val Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg117His Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg138Gln Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg143His Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg156His Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg176Gln Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg176Trp Uncertain significance ★ ⚠ same type
IGFBP5 p.Arg212Cys 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/igfbp5-p-pro232ser (accessed [today's date]).

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