Is CHMP2B p.Ile29Val (c.85A>G) pathogenic?

CHMP2B p.Ile29Val (c.85A>G) is classified Uncertain significance in CHMP2B (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.041%, nfe); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7.

What condition is associated with CHMP2B p.Ile29Val (c.85A>G)?

CHMP2B p.Ile29Val (c.85A>G) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (ClinVar).

How common is CHMP2B p.Ile29Val (c.85A>G) in the general population?

CHMP2B p.Ile29Val (c.85A>G) is ultra-rare (popmax 0.041%, nfe) (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.Ile29Val (c.85A>G)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

CHMP2B p.Ile29Val

c.85A>G · rs63750818 · VCV21507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -4.64	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 2.6	GERP -2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	15.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.041% European (non-Finnish) · 484/1,179,738 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.0319% 515/1,613,658 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.041%	2,437
Remaining individualsnot grpmax-eligible	0.0256%	3,904
African / African-American	0.012%	8,323
Admixed American	0.01%	9,999

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.Ile29Val
Coding: c.85A>G
MANE Select: NM_014043
dbSNP: rs63750818
Type: single nucleotide variant
Location: chr3:87240749 (GRCh38)
Gene constraint: LOEUF 1.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 1 PDB
Residue 29: a UniProt-annotated variant site (in ftdals7; cells expressing the mutant protein have large cytoplasmic vacuoles with an accumulation of the mutant protein on the outer membrane termed halos; cells with the mutant protein also have aberrant localization of cd63 and an increase in map1lc3a1 overall indicating a defect in the autophagic pathway)

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 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
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-ile29val (accessed [today's date]).

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