Is INF2 p.Pro459= (c.1377G>C) pathogenic?

INF2 p.Pro459= (c.1377G>C) is classified Likely benign in INF2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-29). Low-frequency (popmax 1.07%, amr); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Pro459= (c.1377G>C)?

INF2 p.Pro459= (c.1377G>C) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E, focal segmental glomerulosclerosis (ClinVar).

How common is INF2 p.Pro459= (c.1377G>C) in the general population?

INF2 p.Pro459= (c.1377G>C) is low-frequency (popmax 1.07%, amr) (gnomAD).

INF2 p.Pro459=

c.1377G>C · rs776870726 · VCV1191639

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, amr)

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -7
Overall
CADD	0.413	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.07% Admixed American · 247/23,132 alleles

Filtering AF 0.959% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.916%

Overall 0.289% 1,131/391,116 alleles · low-frequency exomes 1,098/310,496 · genomes 33/80,620 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.07%	94
Ashkenazi Jewishnot grpmax-eligible	0.826%	121
Middle Eastern	0.61%	164
Remaining individualsnot grpmax-eligible	0.423%	237
Finnishnot grpmax-eligible	0.42%	238
South Asian	0.349%	286
Amishnot grpmax-eligible	0.211%	474
European (non-Finnish)	0.19%	526
African / African-American	0.133%	752
East Asian	0.0988%	1,013

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: INF2
Protein: p.Pro459=
Coding: c.1377G>C
MANE Select: NM_022489
dbSNP: rs776870726
Type: single nucleotide variant
Location: chr14:104707644 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 459: the 'disordered' region

Full INF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease dominant intermediate E focal segmental glomerulosclerosis

Similar variants

INF2 p.Pro459Leu Uncertain significance ★★ ⚠ same residue
INF2 p.Pro459_Pro462del Uncertain significance ★★ same residue
INF2 p.Arg177Cys Pathogenic/Likely pathogenic ★★ same condition
INF2 p.Arg214Cys Pathogenic/Likely pathogenic ★★ same condition
INF2 p.Arg214His Pathogenic/Likely pathogenic ★★ same condition
INF2 p.Arg218Gln Pathogenic/Likely pathogenic ★★ same condition
INF2 p.Arg218Trp Pathogenic/Likely pathogenic ★★ same condition
INF2 p.Arg91Gly Pathogenic/Likely pathogenic ★★ 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/inf2-p-pro459 (accessed [today's date]).

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