Is INF2 p.Pro1122Arg (c.3365C>G) pathogenic?

INF2 p.Pro1122Arg (c.3365C>G) is classified Uncertain significance in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-02). AlphaMissense: likely benign (0.0768); Very rare (popmax 0.000254%, nfe); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Pro1122Arg (c.3365C>G)?

INF2 p.Pro1122Arg (c.3365C>G) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Pro1122Arg (c.3365C>G) in the general population?

INF2 p.Pro1122Arg (c.3365C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about INF2 p.Pro1122Arg (c.3365C>G)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

INF2 p.Pro1122Arg

c.3365C>G · VCV3748798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -7.01	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 1.3	GERP 3.3, phastCons 0.001
Regional constraint	o/e 1.03	unconstrained · MANE · 1,758 bp · p 0.55 · regional, not allelic
Overall
CADD	13.42	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 0.000254% European (non-Finnish) · 3/1,179,890 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,718 alleles · very rare exomes 1/1,460,480 · genomes 2/152,238 · 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: INF2
Protein: p.Pro1122Arg
Coding: c.3365C>G
MANE Select: NM_022489
Type: single nucleotide variant
Location: chr14:104714527 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 1122: 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

Similar variants

INF2 p.Pro1122Leu 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
INF2 p.Asn202Asp 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-pro1122arg (accessed [today's date]).

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