Is INF2 p.Pro1235Ser (c.3703C>T) pathogenic?

INF2 p.Pro1235Ser (c.3703C>T) is classified Conflicting classifications of pathogenicity in INF2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-22). AlphaMissense: likely benign (0.0779); Ultra-rare (popmax 0.0331%, mid); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Pro1235Ser (c.3703C>T)?

INF2 p.Pro1235Ser (c.3703C>T) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Pro1235Ser (c.3703C>T) in the general population?

INF2 p.Pro1235Ser (c.3703C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about INF2 p.Pro1235Ser (c.3703C>T)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

INF2 p.Pro1235Ser

c.3703C>T · rs201091360 · VCV472862

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP 5.4, phastCons 0.95
Regional constraint	o/e 1.03	unconstrained · MANE · 1,758 bp · p 0.55 · regional, not allelic
Overall
CADD	17.0	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 0.0331% Middle Eastern · 2/6,040 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00236% 38/1,613,580 alleles · ultra-rare exomes 33/1,461,232 · genomes 5/152,348 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,020
Remaining individualsnot grpmax-eligible	0.0048%	20,818
European (non-Finnish)	0.00271%	36,867
Admixed American	0.00167%	60,020

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.Pro1235Ser
Coding: c.3703C>T
MANE Select: NM_022489
dbSNP: rs201091360
Type: single nucleotide variant
Location: chr14:104715292 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 1235: 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.Pro1235= Likely benign ★ same residue
INF2 p.Pro1235fs 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-pro1235ser (accessed [today's date]).

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