Is INF2 p.Arg91Cys (c.271C>T) pathogenic?

INF2 p.Arg91Cys (c.271C>T) is classified Uncertain significance in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.281); Very rare (popmax 8.5e-05%, nfe); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Arg91Cys (c.271C>T) in the general population?

INF2 p.Arg91Cys (c.271C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about INF2 p.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely benign (score 0.281) — an in-silico prediction, not a clinical call.

INF2 p.Arg91Cys

Q: What condition is associated with INF2 p.Arg91Cys (c.271C>T)?

INF2 p.Arg91Cys (c.271C>T) 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.271C>T · rs200247054 · VCV1063428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease dominant intermediate E

Computational evidence

Protein change
AlphaMissense	0.281	likely benign
REVEL	0.616	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 7.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 5,444 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	27.5	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 8.5e-05% European (non-Finnish) · 1/1,176,360 alleles

Overall 6.25e-05% 1/1,600,772 alleles · very rare exomes 0/1,448,406 · genomes 1/152,366 · 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.Arg91Cys
Coding: c.271C>T
MANE Select: NM_022489
dbSNP: rs200247054
Type: single nucleotide variant
Location: chr14:104701636 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 91: the gbd/fh3 domain

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.Arg91Gly Pathogenic/Likely pathogenic ★★ same residue
INF2 p.Arg91Leu 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.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-arg91cys (accessed [today's date]).

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