Is IGFBP7 p.Pro105Arg (c.314C>G) pathogenic?

IGFBP7 p.Pro105Arg (c.314C>G) is classified Uncertain significance in IGFBP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-30). AlphaMissense: likely benign (0.0743); Very rare (popmax 0.00709%, eas); Associated with Inborn genetic diseases.

What condition is associated with IGFBP7 p.Pro105Arg (c.314C>G)?

IGFBP7 p.Pro105Arg (c.314C>G) is associated with Inborn genetic diseases (ClinVar).

How common is IGFBP7 p.Pro105Arg (c.314C>G) in the general population?

IGFBP7 p.Pro105Arg (c.314C>G) is very rare (popmax 0.00709%, eas) (gnomAD).

What do computational predictors say about IGFBP7 p.Pro105Arg (c.314C>G)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

IGFBP7 p.Pro105Arg

c.314C>G · rs1243637444 · VCV2299418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00709%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.88	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 4.9	GERP -0.46, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 79 kb · p 0.9 · regional, not allelic
Overall
CADD	13.85	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 0.00709% East Asian · 3/42,306 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00102%

Overall 0.000257% 4/1,558,548 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00709%	14,102
Admixed American	0.00185%	54,172

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: IGFBP7
Protein: p.Pro105Arg
Coding: c.314C>G
MANE Select: NM_001553
dbSNP: rs1243637444
Type: single nucleotide variant
Location: chr4:57110038 (GRCh38)
Gene constraint: LOEUF 1.812 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.11 · 3 PDB
Residue 105: a disulfide bond; the igfbp n-terminal domain; the kazal-like domain

Full IGFBP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGFBP7 p.Ala101Val Uncertain significance ★ ⚠ same condition
IGFBP7 p.Ala136Thr Uncertain significance ★ ⚠ same condition
IGFBP7 p.Ala56Glu Uncertain significance ★ ⚠ same condition
IGFBP7 p.Ala56Gly Uncertain significance ★ ⚠ same condition
IGFBP7 p.Ala56Val Uncertain significance ★ ⚠ same condition
IGFBP7 p.Ala76Thr Uncertain significance ★ ⚠ same condition
IGFBP7 p.Arg213Gln Uncertain significance ★ ⚠ same condition
IGFBP7 p.Arg221Gln Uncertain significance ★ ⚠ same condition

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/igfbp7-p-pro105arg (accessed [today's date]).

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