Is INF2 p.Pro461Ser (c.1381C>T) pathogenic?

INF2 p.Pro461Ser (c.1381C>T) is classified Likely benign in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.1169); Very rare (popmax 0.00289%, nfe); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Pro461Ser (c.1381C>T)?

INF2 p.Pro461Ser (c.1381C>T) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Pro461Ser (c.1381C>T) in the general population?

INF2 p.Pro461Ser (c.1381C>T) is very rare (popmax 0.00289%, nfe) (gnomAD).

What do computational predictors say about INF2 p.Pro461Ser (c.1381C>T)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

INF2 p.Pro461Ser

c.1381C>T · rs1212700148 · VCV1979669

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 2.9, phastCons 0.18
Regional constraint	o/e 1.23	unconstrained · MANE · 929 bp · p 5.5e-05 · regional, not allelic
Overall
CADD	11.78	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 0.00289% European (non-Finnish) · 19/657,298 alleles

Filtering AF 0.00185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00195% 19/974,886 alleles · very rare exomes 18/835,850 · genomes 1/139,036 · 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.Pro461Ser
Coding: c.1381C>T
MANE Select: NM_022489
dbSNP: rs1212700148
Type: single nucleotide variant
Location: chr14:104707648 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 461: 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.Pro461= Likely benign ★★ same residue
INF2 p.Pro461Gln Uncertain significance ★ ⚠ same residue
INF2 p.Pro461_Pro462del 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

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-pro461ser (accessed [today's date]).

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