Is CHMP6 p.Met87Thr (c.260T>C) pathogenic?

CHMP6 p.Met87Thr (c.260T>C) is classified Uncertain significance in CHMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.6479); Ultra-rare (popmax 0.0206%, nfe).

How common is CHMP6 p.Met87Thr (c.260T>C) in the general population?

CHMP6 p.Met87Thr (c.260T>C) is ultra-rare (popmax 0.0206%, nfe) (gnomAD).

What do computational predictors say about CHMP6 p.Met87Thr (c.260T>C)?

AlphaMissense predicts likely pathogenic (score 0.6479) — an in-silico prediction, not a clinical call.

CHMP6 p.Met87Thr

c.260T>C · VCV4228233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6479 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0206%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6479	likely pathogenic
REVEL	0.683	pathogenic-leaning
SaProt	LLR -11.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,231 bp · p 0.75 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0206% European (non-Finnish) · 242/1,174,390 alleles

Filtering AF 0.0184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.0155% 248/1,598,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0206%	4,853
Admixed American	0.00352%	28,393
Remaining individualsnot grpmax-eligible	0.00323%	30,992
African / African-American	0.00267%	37,399

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.Met87Thr
Coding: c.260T>C
MANE Select: NM_024591
Type: single nucleotide variant
Location: chr17:80995105 (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.Arg12Pro 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

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-met87thr (accessed [today's date]).

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