Is SEPTIN9 p.Arg76= (c.228C>T) pathogenic?

SEPTIN9 p.Arg76= (c.228C>T) is classified Likely benign in SEPTIN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). Very rare (popmax 0.01%, amr).

How common is SEPTIN9 p.Arg76= (c.228C>T) in the general population?

SEPTIN9 p.Arg76= (c.228C>T) is very rare (popmax 0.01%, amr) (gnomAD).

SEPTIN9 p.Arg76=

c.228C>T · rs752815848 · VCV1682585

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.98	GERP 0.083, phastCons 1
Overall
CADD	8.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,026 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00112% 18/1,613,700 alleles · very rare exomes 17/1,461,428 · genomes 1/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.0064%	15,621
South Asian	0.0011%	91,072
European (non-Finnish)	0.000593%	168,554

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.Arg76=
Coding: c.228C>T
MANE Select: NM_001113491
dbSNP: rs752815848
Type: single nucleotide variant
Location: chr17:77402210 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 3 PDB
Residue 76: the 'disordered' region; a UniProt-annotated variant site (in)

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

Similar variants

SEPTIN9 p.Arg76Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SEPTIN9 p.Arg76His Uncertain significance ★ ⚠ 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

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-arg76 (accessed [today's date]).

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