Is CHMP2B p.Thr73Met (c.218C>T) pathogenic?

CHMP2B p.Thr73Met (c.218C>T) is classified Conflicting classifications of pathogenicity in CHMP2B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.1798); Ultra-rare (popmax 0.0533%, amr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7.

What condition is associated with CHMP2B p.Thr73Met (c.218C>T)?

CHMP2B p.Thr73Met (c.218C>T) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (ClinVar).

How common is CHMP2B p.Thr73Met (c.218C>T) in the general population?

CHMP2B p.Thr73Met (c.218C>T) is ultra-rare (popmax 0.0533%, amr) (gnomAD).

How is Behavioral variant of frontotemporal dementia inherited?

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

What do computational predictors say about CHMP2B p.Thr73Met (c.218C>T)?

AlphaMissense predicts likely benign (score 0.1798) — an in-silico prediction, not a clinical call.

CHMP2B p.Thr73Met

c.218C>T · rs192188850 · VCV346806

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Computational evidence

Protein change
AlphaMissense	0.1798	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0533% Admixed American · 32/59,990 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00421% 68/1,613,712 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0533%	1,875
Remaining individualsnot grpmax-eligible	0.0112%	8,928
African / African-American	0.004%	24,993
European (non-Finnish)	0.00203%	49,160
Finnishnot grpmax-eligible	0.00156%	63,996
South Asian	0.0011%	91,044

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.Thr73Met
Coding: c.218C>T
MANE Select: NM_014043
dbSNP: rs192188850
Type: single nucleotide variant
Location: chr3:87245805 (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.Thr73= Likely benign ★★ 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-thr73met (accessed [today's date]).

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