Is CHMP6 p.Arg45Cys (c.133C>T) pathogenic?

CHMP6 p.Arg45Cys (c.133C>T) is classified Uncertain significance in CHMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: ambiguous (0.3935); Ultra-rare (popmax 0.0385%, amr).

How common is CHMP6 p.Arg45Cys (c.133C>T) in the general population?

CHMP6 p.Arg45Cys (c.133C>T) is ultra-rare (popmax 0.0385%, amr) (gnomAD).

What do computational predictors say about CHMP6 p.Arg45Cys (c.133C>T)?

AlphaMissense predicts ambiguous (score 0.3935) — an in-silico prediction, not a clinical call.

CHMP6 p.Arg45Cys

c.133C>T · rs367935751 · VCV2310528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, amr)

Computational evidence

Protein change
AlphaMissense	0.3935	ambiguous
REVEL	0.616	indeterminate
SaProt	LLR -13.36	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.72, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,231 bp · p 0.75 · regional, not allelic
Overall
CADD	25.3	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 0.0385% Admixed American · 21/54,502 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0216%

Overall 0.00581% 92/1,583,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0385%	2,595
East Asian	0.0137%	7,276
European (non-Finnish)	0.00523%	19,133
Remaining individualsnot grpmax-eligible	0.00326%	30,718
African / African-American	0.00269%	37,217

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: CHMP6
Protein: p.Arg45Cys
Coding: c.133C>T
MANE Select: NM_024591
dbSNP: rs367935751
Type: single nucleotide variant
Location: chr17:80994650 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 82.51 · 2 PDB

Full CHMP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHMP6 p.Arg45His Uncertain significance ★ ⚠ same residue
CHMP6 p.Asn185= Benign ★★ same type
CHMP6 p.Gly55Ser Benign ★★ ⚠ same type
CHMP6 p.Ala190Asp Uncertain significance ★ ⚠ same type
CHMP6 p.Ala46Thr Uncertain significance ★ ⚠ same type
CHMP6 p.Arg12Pro Uncertain significance ★ ⚠ same type
CHMP6 p.Arg138Gln Uncertain significance ★ ⚠ same type
CHMP6 p.Arg49Gln 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/chmp6-p-arg45cys (accessed [today's date]).

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