Is INF2 p.Ala418= (c.1254G>A) pathogenic?

INF2 p.Ala418= (c.1254G>A) is classified Likely benign in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-26). Very rare (popmax 0.00396%, amr); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Ala418= (c.1254G>A)?

INF2 p.Ala418= (c.1254G>A) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Ala418= (c.1254G>A) in the general population?

INF2 p.Ala418= (c.1254G>A) is very rare (popmax 0.00396%, amr) (gnomAD).

INF2 p.Ala418=

c.1254G>A · rs1370627984 · VCV1145394

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00396%, amr)

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.34	donor gain · deltas
Pangolin	Δ0.30	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.9	GERP -4.1
Overall
CADD	13.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00396% Admixed American · 2/50,564 alleles

Filtering AF 0.000656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000268%

Overall 0.000975% 15/1,538,202 alleles · very rare exomes 11/1,390,780 · genomes 4/147,422 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00396%	25,282
African / African-American	0.0028%	35,681
Remaining individualsnot grpmax-eligible	0.00167%	59,792
South Asian	0.00119%	83,692
European (non-Finnish)	0.000787%	127,130

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.Ala418=
Coding: c.1254G>A
MANE Select: NM_022489
dbSNP: rs1370627984
Type: single nucleotide variant
Location: chr14:104707521 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 418: the 'disordered' region

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.Ala418Val 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
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-ala418 (accessed [today's date]).

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