Is INF2 p.Ala727Val (c.2180C>T) pathogenic?

INF2 p.Ala727Val (c.2180C>T) is classified Conflicting classifications of pathogenicity in INF2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.1438); Very rare (popmax 0.00389%, amr); Associated with Charcot-Marie-Tooth disease dominant intermediate E.

How common is INF2 p.Ala727Val (c.2180C>T) in the general population?

INF2 p.Ala727Val (c.2180C>T) is very rare (popmax 0.00389%, amr) (gnomAD).

What do computational predictors say about INF2 p.Ala727Val (c.2180C>T)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

INF2 p.Ala727Val

Q: What condition is associated with INF2 p.Ala727Val (c.2180C>T)?

INF2 p.Ala727Val (c.2180C>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.2180C>T · rs1156240396 · VCV939664

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00389%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease dominant intermediate E

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 6.9, phastCons 0.35
Regional constraint	o/e 0.70	unconstrained · MANE · 3,038 bp · p 6.5e-07 · regional, not allelic
Overall
CADD	21.5	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 0.00389% Admixed American · 2/51,478 alleles

Filtering AF 0.000644% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000241%

Overall 0.000644% 10/1,552,960 alleles · very rare exomes 9/1,400,738 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00389%	25,739
Remaining individualsnot grpmax-eligible	0.00166%	60,236
African / African-American	0.00137%	73,182
South Asian	0.00119%	84,202
European (non-Finnish)	0.000435%	229,789

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.Ala727Val
Coding: c.2180C>T
MANE Select: NM_022489
dbSNP: rs1156240396
Type: single nucleotide variant
Location: chr14:104710129 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 727: 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.Ala727= Likely benign ★★ same residue
INF2 p.Ala727Thr 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.Arg91Gly 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-ala727val (accessed [today's date]).

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