Is IGFBP3 p.Pro65Ser (c.193C>T) pathogenic?

IGFBP3 p.Pro65Ser (c.193C>T) is classified Uncertain significance in IGFBP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.7627); Very rare (popmax 0.00328%, amr).

How common is IGFBP3 p.Pro65Ser (c.193C>T) in the general population?

IGFBP3 p.Pro65Ser (c.193C>T) is very rare (popmax 0.00328%, amr) (gnomAD).

What do computational predictors say about IGFBP3 p.Pro65Ser (c.193C>T)?

AlphaMissense predicts likely pathogenic (score 0.7627) — an in-silico prediction, not a clinical call.

IGFBP3 p.Pro65Ser

c.193C>T · rs1276869933 · VCV2251320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00328%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7627	likely pathogenic
REVEL	0.443	indeterminate
SaProt	LLR -13.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.77, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,317 bp · p 0.023 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00328% Admixed American · 1/30,442 alleles

Filtering AF 0.000503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000188%

Overall 0.00036% 5/1,388,332 alleles · very rare exomes 4/1,236,602 · genomes 1/151,730 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00328%	30,442
African / African-American	0.00303%	32,988
Remaining individualsnot grpmax-eligible	0.0019%	52,716
European (non-Finnish)	9.28e-05%	1,077,070

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: IGFBP3
Protein: p.Pro65Ser
Coding: c.193C>T
MANE Select: NM_000598
dbSNP: rs1276869933
Type: single nucleotide variant
Location: chr7:45920948 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 67.94 · 1 PDB
Residue 65: the igfbp n-terminal domain; the 'igf-binding' region

Full IGFBP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFBP3 c.403+13C>A Uncertain significance ★ same type
IGFBP3 p.Ala10Gly Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala10Ser Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala117Thr Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala130Val Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala137Val Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala47Pro Uncertain significance ★ ⚠ same type
IGFBP3 p.Ala4Val 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/igfbp3-p-pro65ser (accessed [today's date]).

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