Is CHMP6 p.Arg12Pro (c.35G>C) pathogenic?

CHMP6 p.Arg12Pro (c.35G>C) is classified Uncertain significance in CHMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.5823); Very rare (popmax 0.000544%, nfe).

How common is CHMP6 p.Arg12Pro (c.35G>C) in the general population?

CHMP6 p.Arg12Pro (c.35G>C) is very rare (popmax 0.000544%, nfe) (gnomAD).

What do computational predictors say about CHMP6 p.Arg12Pro (c.35G>C)?

AlphaMissense predicts likely pathogenic (score 0.5823) — an in-silico prediction, not a clinical call.

CHMP6 p.Arg12Pro

c.35G>C · rs757131739 · VCV2555047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000544%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5823	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -0.65, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,231 bp · p 0.75 · regional, not allelic
Overall
CADD	24.8	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 0.000544% European (non-Finnish) · 6/1,102,732 alleles

Filtering AF 0.000196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000129%

Overall 0.000477% 7/1,466,428 alleles · very rare exomes 6/1,315,282 · genomes 1/151,146 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00182%	54,918
European (non-Finnish)grpmax	0.000544%	183,789

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg12Pro
Coding: c.35G>C
MANE Select: NM_024591
dbSNP: rs757131739
Type: single nucleotide variant
Location: chr17:80991953 (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.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.Arg138Gln Uncertain significance ★ ⚠ same type
CHMP6 p.Arg45Cys Uncertain significance ★ same type
CHMP6 p.Arg45His 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-arg12pro (accessed [today's date]).

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