Is INF2 p.Val125Met (c.373G>A) pathogenic?

INF2 p.Val125Met (c.373G>A) is classified Uncertain significance in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-08). AlphaMissense: ambiguous (0.439); Very rare (popmax 0.00126%, sas); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Val125Met (c.373G>A)?

INF2 p.Val125Met (c.373G>A) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Val125Met (c.373G>A) in the general population?

INF2 p.Val125Met (c.373G>A) is very rare (popmax 0.00126%, sas) (gnomAD).

What do computational predictors say about INF2 p.Val125Met (c.373G>A)?

AlphaMissense predicts ambiguous (score 0.439) — an in-silico prediction, not a clinical call.

INF2 p.Val125Met

c.373G>A · rs762621935 · VCV1388658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00126%, sas)

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.439	ambiguous
REVEL	0.614	indeterminate
SaProt	LLR -8.59	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 7.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 5,444 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	25.9	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 0.00126% South Asian · 1/79,442 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000329% 5/1,520,718 alleles · very rare exomes 5/1,368,340 · genomes 0/152,378 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00193%	51,860
South Asiangrpmax	0.00126%	79,442
European (non-Finnish)	0.000265%	377,652

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val125Met
Coding: c.373G>A
MANE Select: NM_022489
dbSNP: rs762621935
Type: single nucleotide variant
Location: chr14:104701738 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 125: the gbd/fh3 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.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
INF2 p.Glu184Lys 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-val125met (accessed [today's date]).

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