Is INF2 p.Arg752His (c.2255G>A) pathogenic?

INF2 p.Arg752His (c.2255G>A) is classified Likely benign in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-30). AlphaMissense: likely benign (0.059); Ultra-rare (popmax 0.0134%, eas); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Arg752His (c.2255G>A)?

INF2 p.Arg752His (c.2255G>A) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Arg752His (c.2255G>A) in the general population?

INF2 p.Arg752His (c.2255G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about INF2 p.Arg752His (c.2255G>A)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

INF2 p.Arg752His

c.2255G>A · rs1450593874 · VCV651891

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -9.39	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 0.69	GERP 4
Regional constraint	o/e 0.36	unconstrained · MANE · 707 bp · p 3e-09 · regional, not allelic
Overall
CADD	14.53	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 0.0134% East Asian · 6/44,874 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000744% 12/1,612,248 alleles · ultra-rare exomes 11/1,460,102 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,479
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Admixed American	0.00333%	29,993
Remaining individualsnot grpmax-eligible	0.0016%	62,424
South Asian	0.0011%	91,068
European (non-Finnish)	8.48e-05%	1,179,736

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.Arg752His
Coding: c.2255G>A
MANE Select: NM_022489
dbSNP: rs1450593874
Type: single nucleotide variant
Location: chr14:104710952 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 752: the fh2 domain

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.Arg752Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
INF2 p.Arg752= 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
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-arg752his (accessed [today's date]).

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