Is INF2 p.Ala727= (c.2181G>A) pathogenic?

INF2 p.Ala727= (c.2181G>A) is classified Likely benign in INF2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-29). Rare (popmax 0.112%, afr); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Ala727= (c.2181G>A)?

INF2 p.Ala727= (c.2181G>A) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Ala727= (c.2181G>A) in the general population?

INF2 p.Ala727= (c.2181G>A) is rare (popmax 0.112%, afr) (gnomAD).

INF2 p.Ala727=

c.2181G>A · rs370830904 · VCV540066

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

Conditions

focal segmental glomerulosclerosis 5

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 -6.6	GERP -14
Overall
CADD	3.048	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% African / African-American · 82/73,314 alleles

Filtering AF 0.0923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0851%

Overall 0.0119% 185/1,553,182 alleles · rare exomes 127/1,400,836 · genomes 58/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	894
South Asian	0.0594%	1,684
Remaining individualsnot grpmax-eligible	0.0133%	7,533
East Asian	0.00973%	10,282
Admixed American	0.00388%	25,754
European (non-Finnish)	0.00339%	29,461

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.Ala727=
Coding: c.2181G>A
MANE Select: NM_022489
dbSNP: rs370830904
Type: single nucleotide variant
Location: chr14:104710130 (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

focal segmental glomerulosclerosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease dominant intermediate E

Similar variants

INF2 p.Ala727Thr Uncertain significance ★ ⚠ same residue
INF2 p.Ala727Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala727 (accessed [today's date]).

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