Is INF2 p.Pro461= (c.1383A>C) pathogenic?

INF2 p.Pro461= (c.1383A>C) is classified Likely benign in INF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). Low-frequency (popmax 3.06%, amr); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Pro461= (c.1383A>C) in the general population?

INF2 p.Pro461= (c.1383A>C) is low-frequency (popmax 3.06%, amr) (gnomAD).

INF2 p.Pro461=

Q: What condition is associated with INF2 p.Pro461= (c.1383A>C)?

INF2 p.Pro461= (c.1383A>C) 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.1383A>C · VCV4783210

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.06%, amr)

Conditions

Charcot-Marie-Tooth disease dominant intermediate E

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 -4.2	GERP -7.6
Overall
CADD	1.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.06% Admixed American · 446/14,568 alleles

Filtering AF 2.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.73%

Overall 0.676% 1,878/277,650 alleles · low-frequency exomes 1,818/229,752 · genomes 60/47,898 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	3.06%	33
Ashkenazi Jewishnot grpmax-eligible	2.28%	44
Middle Eastern	1.47%	68
South Asian	1.22%	82
Finnishnot grpmax-eligible	1.07%	93
Remaining individualsnot grpmax-eligible	0.797%	125
European (non-Finnish)	0.391%	256
African / African-American	0.356%	281
Amishnot grpmax-eligible	0.331%	302
East Asian	0.193%	519

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.Pro461=
Coding: c.1383A>C
MANE Select: NM_022489
Type: single nucleotide variant
Location: chr14:104707650 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 461: 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.Pro461Gln Uncertain significance ★ ⚠ same residue
INF2 p.Pro461Ser Likely benign ★ same residue
INF2 p.Pro461_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

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-pro461 (accessed [today's date]).

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