Is SEPTIN9 p.Phe366Ser (c.1097T>C) pathogenic?

SEPTIN9 p.Phe366Ser (c.1097T>C) is classified Uncertain significance in SEPTIN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-25). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 8.48e-05%, nfe).

How common is SEPTIN9 p.Phe366Ser (c.1097T>C) in the general population?

SEPTIN9 p.Phe366Ser (c.1097T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SEPTIN9 p.Phe366Ser (c.1097T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

SEPTIN9 p.Phe366Ser

c.1097T>C · rs2510110862 · VCV2445587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 4% in SEPTIN9
REVEL	0.745	pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 96 kb · p 4.4e-13 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,848 alleles

Overall 6.2e-05% 1/1,613,706 alleles · very rare exomes 1/1,461,428 · genomes 0/152,278 · 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: SEPTIN9
Protein: p.Phe366Ser
Coding: c.1097T>C
MANE Select: NM_001113491
dbSNP: rs2510110862
Type: single nucleotide variant
Location: chr17:77488294 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 3 PDB
Residue 366: the septin-type g domain

Full SEPTIN9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEPTIN9 p.Phe366= Likely benign ★ same residue
SEPTIN9 p.Arg106Trp Pathogenic ★★ same type
SEPTIN9 c.1380+5G>C Uncertain significance ★★ same type
SEPTIN9 p.Ala183Val Uncertain significance ★★ ⚠ same type
SEPTIN9 p.Ala201Thr Uncertain significance ★★ ⚠ same type
SEPTIN9 p.Ala234Val Uncertain significance ★★ ⚠ same type
SEPTIN9 p.Ala266Thr Uncertain significance ★★ ⚠ same type
SEPTIN9 p.Ala571Thr Uncertain significance ★★ ⚠ same type

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/septin9-p-phe366ser (accessed [today's date]).

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