Is INF2 p.Pro464Arg (c.1391C>G) pathogenic?

INF2 p.Pro464Arg (c.1391C>G) is classified Uncertain significance in INF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1578); Very rare (popmax 0.00644%, amr); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Pro464Arg (c.1391C>G) in the general population?

INF2 p.Pro464Arg (c.1391C>G) is very rare (popmax 0.00644%, amr) (gnomAD).

What do computational predictors say about INF2 p.Pro464Arg (c.1391C>G)?

AlphaMissense predicts likely benign (score 0.1578) — an in-silico prediction, not a clinical call.

INF2 p.Pro464Arg

Q: What condition is associated with INF2 p.Pro464Arg (c.1391C>G)?

INF2 p.Pro464Arg (c.1391C>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.1391C>G · rs1372258814 · VCV2432851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1578 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease dominant intermediate E

Computational evidence

Protein change
AlphaMissense	0.1578	likely benign
REVEL	0.422	indeterminate
SaProt	LLR -11.87	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 4.2, phastCons 0.69
Regional constraint	o/e 1.23	unconstrained · MANE · 929 bp · p 5.5e-05 · regional, not allelic
Overall
CADD	15.07	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

Grpmax group 0.00644% Admixed American · 3/46,562 alleles

Filtering AF 0.00171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000874%

Overall 0.000288% 3/1,041,924 alleles · very rare exomes 3/903,060 · genomes 0/138,864 · 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.Pro464Arg
Coding: c.1391C>G
MANE Select: NM_022489
dbSNP: rs1372258814
Type: single nucleotide variant
Location: chr14:104707658 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 464: the 'disordered' region

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-pro464arg (accessed [today's date]).

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