Is SEPTIN2 p.Ala166= (c.498G>A) pathogenic?

SEPTIN2 p.Ala166= (c.498G>A) is classified Benign in SEPTIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-28). Rare (popmax 0.282%, nfe).

How common is SEPTIN2 p.Ala166= (c.498G>A) in the general population?

SEPTIN2 p.Ala166= (c.498G>A) is rare (popmax 0.282%, nfe) (gnomAD).

SEPTIN2 p.Ala166=

c.498G>A · rs34185831 · VCV708068

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.282%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.067	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -4.3
Overall
CADD	4.423	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.282% European (non-Finnish) · 3,329/1,179,804 alleles

Filtering AF 0.274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.271%

Overall 0.277% 4,471/1,613,742 alleles · rare exomes 4,039/1,461,560 · genomes 432/152,182 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.89%	53
Finnishnot grpmax-eligible	0.409%	244
Remaining individualsnot grpmax-eligible	0.331%	302
European (non-Finnish)grpmax	0.282%	354
Amishnot grpmax-eligible	0.219%	456
South Asian	0.0604%	1,655
Admixed American	0.0584%	1,714
Middle Eastern	0.0495%	2,020
African / African-American	0.0253%	3,948
East Asian	0.00223%	44,882

Ashkenazi Jewish 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: SEPTIN2
Protein: p.Ala166=
Coding: c.498G>A
MANE Select: NM_004404
dbSNP: rs34185831
Type: single nucleotide variant
Location: chr2:241337694 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.30 · 7 PDB
Residue 166: the septin-type g domain; an α-helix

Full SEPTIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEPTIN2 p.Ala337Pro Uncertain significance ★ ⚠ same type
SEPTIN2 p.Ala341Val Uncertain significance ★ ⚠ same type
SEPTIN2 p.Arg128Thr Uncertain significance ★ ⚠ same type
SEPTIN2 p.Arg194Gln Uncertain significance ★ ⚠ same type
SEPTIN2 p.Arg198Lys Uncertain significance ★ ⚠ same type
SEPTIN2 p.Arg338Lys Uncertain significance ★ ⚠ same type
SEPTIN2 p.Asn22Lys Uncertain significance ★ ⚠ same type
SEPTIN2 p.Asn271Ser 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/septin2-p-ala166 (accessed [today's date]).

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