Is INF2 p.Pro755Arg (c.2264C>G) pathogenic?

INF2 p.Pro755Arg (c.2264C>G) is classified Uncertain significance in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.6547); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Pro755Arg (c.2264C>G) in the general population?

INF2 p.Pro755Arg (c.2264C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INF2 p.Pro755Arg (c.2264C>G)?

AlphaMissense predicts likely pathogenic (score 0.6547) — an in-silico prediction, not a clinical call.

INF2 p.Pro755Arg

Q: What condition is associated with INF2 p.Pro755Arg (c.2264C>G)?

INF2 p.Pro755Arg (c.2264C>G) is associated with Charcot-Marie-Tooth disease dominant intermediate E, focal segmental glomerulosclerosis 5 (ClinVar).

Q: How is Autosomal dominant intermediate Charcot-Marie-Tooth disease type E inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.2264C>G · rs2541937428 · VCV2921933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease dominant intermediate E

Computational evidence

Protein change
AlphaMissense	0.6547	likely pathogenic
REVEL	0.259	benign-leaning
SaProt	LLR -11.42	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 5.6, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 707 bp · p 3e-09 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INF2
Protein: p.Pro755Arg
Coding: c.2264C>G
MANE Select: NM_022489
dbSNP: rs2541937428
Type: single nucleotide variant
Location: chr14:104710961 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 755: the fh2 domain; an α-helix

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

Disease context

Charcot-Marie-Tooth disease dominant intermediate E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: focal segmental glomerulosclerosis 5

For Autosomal dominant intermediate Charcot-Marie-Tooth disease type E (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: No data available

Similar variants

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
INF2 p.Glu184Lys 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-pro755arg (accessed [today's date]).

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