Is CHMP2B p.Arg205Trp (c.613C>T) pathogenic?

CHMP2B p.Arg205Trp (c.613C>T) is classified Uncertain significance in CHMP2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-13). AlphaMissense: ambiguous (0.4813); Ultra-rare (popmax 0.0112%, eas); Associated with parkinsonian disorder.

What condition is associated with CHMP2B p.Arg205Trp (c.613C>T)?

CHMP2B p.Arg205Trp (c.613C>T) is associated with parkinsonian disorder, frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (ClinVar).

How common is CHMP2B p.Arg205Trp (c.613C>T) in the general population?

CHMP2B p.Arg205Trp (c.613C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about CHMP2B p.Arg205Trp (c.613C>T)?

AlphaMissense predicts ambiguous (score 0.4813) — an in-silico prediction, not a clinical call.

CHMP2B p.Arg205Trp

c.613C>T · rs373536428 · VCV1037550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

parkinsonian disorder

Computational evidence

Protein change
AlphaMissense	0.4813	ambiguous
REVEL	0.536	indeterminate
SaProt	LLR -13.35	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.96	GERP -0.85, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	24.1	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 0.0112% East Asian · 5/44,824 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00341% 55/1,611,638 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,965
African / African-American	0.00803%	12,460
European (non-Finnish)	0.00339%	29,459
South Asian	0.0033%	30,348
Admixed American	0.00167%	59,842

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.Arg205Trp
Coding: c.613C>T
MANE Select: NM_014043
dbSNP: rs373536428
Type: single nucleotide variant
Location: chr3:87253793 (GRCh38)
Gene constraint: LOEUF 1.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 1 PDB
Residue 205: an α-helix

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

Disease context

parkinsonian disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Similar variants

CHMP2B p.Arg205Gln Uncertain significance ★★ ⚠ same residue
CHMP2B p.Arg205Leu Uncertain significance ★★ ⚠ same residue
CHMP2B c.126+4A>G 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
CHMP2B p.Ile29Val Uncertain significance ★★ ⚠ same condition
CHMP2B p.Lys59Glu 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-arg205trp (accessed [today's date]).

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