Is INF2 p.Ser23Ala (c.67T>G) pathogenic?

INF2 p.Ser23Ala (c.67T>G) is classified Uncertain significance in INF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-21). AlphaMissense: likely benign (0.0619); Very rare (popmax 0.00402%, afr); Associated with focal segmental glomerulosclerosis 5.

What condition is associated with INF2 p.Ser23Ala (c.67T>G)?

INF2 p.Ser23Ala (c.67T>G) is associated with focal segmental glomerulosclerosis 5, Charcot-Marie-Tooth disease dominant intermediate E (ClinVar).

How common is INF2 p.Ser23Ala (c.67T>G) in the general population?

INF2 p.Ser23Ala (c.67T>G) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about INF2 p.Ser23Ala (c.67T>G)?

AlphaMissense predicts likely benign (score 0.0619) — an in-silico prediction, not a clinical call.

INF2 p.Ser23Ala

c.67T>G · rs746964937 · VCV857212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 5

Computational evidence

Protein change
AlphaMissense	0.0619	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -6.22	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 -0.87	GERP 4.4
Regional constraint	o/e 0.96	unconstrained · MANE · 99 bp · p 0.8 · regional, not allelic
Overall
CADD	12.54	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00402% African / African-American · 3/74,574 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000654%

Overall 0.00119% 19/1,596,232 alleles · very rare exomes 18/1,444,000 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,858
European (non-Finnish)	0.00137%	73,210

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.Ser23Ala
Coding: c.67T>G
MANE Select: NM_022489
dbSNP: rs746964937
Type: single nucleotide variant
Location: chr14:104701432 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.34 · 10 PDB
Residue 23: the gbd/fh3 domain; 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.Ser23Thr Likely benign ★★ same residue
INF2 p.Ser23= 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-ser23ala (accessed [today's date]).

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