Is IGFBP6 p.Pro30Ser (c.88C>T) pathogenic?

IGFBP6 p.Pro30Ser (c.88C>T) is classified Uncertain significance in IGFBP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0975); Ultra-rare (popmax 0.0165%, afr).

How common is IGFBP6 p.Pro30Ser (c.88C>T) in the general population?

IGFBP6 p.Pro30Ser (c.88C>T) is ultra-rare (popmax 0.0165%, afr) (gnomAD).

What do computational predictors say about IGFBP6 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

IGFBP6 p.Pro30Ser

c.88C>T · VCV4274164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP 0.91, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,446 bp · p 0.73 · regional, not allelic
Overall
CADD	23.8	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 0.0165% African / African-American · 12/72,826 alleles

Filtering AF 0.00946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00741%

Overall 0.000778% 12/1,542,850 alleles · ultra-rare exomes 0/1,390,580 · genomes 12/152,270 · 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: IGFBP6
Protein: p.Pro30Ser
Coding: c.88C>T
MANE Select: NM_002178
Type: single nucleotide variant
Location: chr12:53097805 (GRCh38)
Gene constraint: LOEUF 1.436 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.56 · 2 PDB
Residue 30: the igfbp n-terminal domain

Full IGFBP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFBP6 p.Ala153= Benign ★★ same type
IGFBP6 p.Arg217Gln Benign/Likely benign ★★ same type
IGFBP6 p.Ala107Asp Uncertain significance ★ ⚠ same type
IGFBP6 p.Ala111Thr Uncertain significance ★ ⚠ same type
IGFBP6 p.Arg108Cys Uncertain significance ★ ⚠ same type
IGFBP6 p.Arg128His Uncertain significance ★ ⚠ same type
IGFBP6 p.Arg134Cys Uncertain significance ★ ⚠ same type
IGFBP6 p.Arg134His 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/igfbp6-p-pro30ser (accessed [today's date]).

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