Is INF2 p.Pro491= (c.1473T>A) pathogenic?

INF2 p.Pro491= (c.1473T>A) is classified Likely benign in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-27). Ultra-rare (popmax 0.0749%, mid); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Pro491= (c.1473T>A) in the general population?

INF2 p.Pro491= (c.1473T>A) is ultra-rare (popmax 0.0749%, mid) (gnomAD).

INF2 p.Pro491=

Q: What condition is associated with INF2 p.Pro491= (c.1473T>A)?

INF2 p.Pro491= (c.1473T>A) 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.1473T>A · rs1595171430 · VCV1118683

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0749%, mid)

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 -0.76
Overall
CADD	0.097	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0749% Middle Eastern · 2/2,670 alleles

Filtering AF 0.0211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.0198% 175/884,428 alleles · ultra-rare exomes 171/833,870 · genomes 4/50,558 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0749%	1,335
European (non-Finnish)	0.0242%	4,126
Remaining individualsnot grpmax-eligible	0.0172%	5,821
Ashkenazi Jewishnot grpmax-eligible	0.0108%	9,286
African / African-American	0.00922%	10,848
East Asian	0.00446%	22,416
South Asian	0.00337%	29,632

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.Pro491=
Coding: c.1473T>A
MANE Select: NM_022489
dbSNP: rs1595171430
Type: single nucleotide variant
Location: chr14:104707740 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB

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.Pro491Leu Uncertain significance ★ ⚠ same residue
INF2 p.Pro491Ser Uncertain significance ★ ⚠ same residue
INF2 p.Pro491His Likely benign ★ ⚠ 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-pro491 (accessed [today's date]).

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