Is CHMP2B p.Thr9= (c.27C>T) pathogenic?

CHMP2B p.Thr9= (c.27C>T) is classified Benign in CHMP2B (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 23.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7.

What condition is associated with CHMP2B p.Thr9= (c.27C>T)?

CHMP2B p.Thr9= (c.27C>T) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (ClinVar).

How is Behavioral variant of frontotemporal dementia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHMP2B p.Thr9=

Q: How common is CHMP2B p.Thr9= (c.27C>T) in the general population?

CHMP2B p.Thr9= (c.27C>T) is common (popmax 23.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.27C>T · rs2279720 · VCV97999

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 23.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -2.6
Overall
CADD	12.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.1% East Asian · 10,361/44,818 alleles

Filtering AF 22.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.6%

Overall 8.45% 136,409/1,614,034 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	23.1%	4
Middle Eastern	14.6%	7
Ashkenazi Jewishnot grpmax-eligible	11.4%	9
African / African-American	11.1%	9
Admixed American	10.6%	9
Remaining individualsnot grpmax-eligible	9.57%	10
South Asian	8.37%	12
European (non-Finnish)	7.66%	13
Finnishnot grpmax-eligible	4.9%	20
Amishnot grpmax-eligible	0.548%	182

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: CHMP2B
Protein: p.Thr9=
Coding: c.27C>T
MANE Select: NM_014043
dbSNP: rs2279720
Type: single nucleotide variant
Location: chr3:87227549 (GRCh38)
Gene constraint: LOEUF 1.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 1 PDB

Full CHMP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Behavioral variant of frontotemporal dementia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Netherlands)

Similar variants

CHMP2B p.Thr9Ser Uncertain significance ★ ⚠ same residue
CHMP2B c.126+4A>G Uncertain significance ★★ same condition
CHMP2B p.Arg205Gln Uncertain significance ★★ ⚠ same condition
CHMP2B p.Arg205Leu Uncertain significance ★★ ⚠ same condition
CHMP2B p.Arg205Trp Uncertain significance ★★ ⚠ same condition
CHMP2B p.Arg69Trp Uncertain significance ★★ ⚠ same condition
CHMP2B p.Asn113Lys Uncertain significance ★★ ⚠ same condition
CHMP2B p.Asn143Ser Uncertain significance ★★ ⚠ 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/chmp2b-p-thr9 (accessed [today's date]).

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