Is IGFBP4 p.Pro40Ser (c.118C>T) pathogenic?

IGFBP4 p.Pro40Ser (c.118C>T) is classified Uncertain significance in IGFBP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0945); Very rare (popmax 0.000262%, nfe).

How common is IGFBP4 p.Pro40Ser (c.118C>T) in the general population?

IGFBP4 p.Pro40Ser (c.118C>T) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about IGFBP4 p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

IGFBP4 p.Pro40Ser

c.118C>T · rs578013057 · VCV2218782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.60	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 3.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.0085 · regional, not allelic
Overall
CADD	22.0	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 0.000262% European (non-Finnish) · 3/1,145,472 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000196% 3/1,531,830 alleles · very rare exomes 2/1,379,644 · genomes 1/152,186 · 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: IGFBP4
Protein: p.Pro40Ser
Coding: c.118C>T
MANE Select: NM_001552
dbSNP: rs578013057
Type: single nucleotide variant
Location: chr17:40443853 (GRCh38)
Gene constraint: LOEUF 0.919 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 77.46 · 4 PDB
Residue 40: the igfbp n-terminal domain; an α-helix

Full IGFBP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFBP4 p.Thr233Met Likely pathogenic ★ same type
IGFBP4 p.Ala181Val Uncertain significance ★ ⚠ same type
IGFBP4 p.Ala8Val Uncertain significance ★ ⚠ same type
IGFBP4 p.Arg167Trp Uncertain significance ★ ⚠ same type
IGFBP4 p.Arg184Gln Uncertain significance ★ same type
IGFBP4 p.Arg184Trp Uncertain significance ★ ⚠ same type
IGFBP4 p.Arg39Leu Uncertain significance ★ ⚠ same type
IGFBP4 p.Arg49Gln 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/igfbp4-p-pro40ser (accessed [today's date]).

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