Is CHMP4B p.Pro186= (c.558C>T) pathogenic?

CHMP4B p.Pro186= (c.558C>T) is classified Benign/Likely benign in CHMP4B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.68%, afr); Associated with cataract 31 multiple types.

What condition is associated with CHMP4B p.Pro186= (c.558C>T)?

CHMP4B p.Pro186= (c.558C>T) is associated with cataract 31 multiple types (ClinVar).

How common is CHMP4B p.Pro186= (c.558C>T) in the general population?

CHMP4B p.Pro186= (c.558C>T) is low-frequency (popmax 2.68%, afr) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CHMP4B p.Pro186=

c.558C>T · rs79766928 · VCV534366

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.68%, afr)

Conditions

cataract 31 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -4
Overall
CADD	6.886	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.68% African / African-American · 2,012/75,036 alleles

Filtering AF 2.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.54%

Overall 0.144% 2,322/1,614,170 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.68%	37
Remaining individualsnot grpmax-eligible	0.171%	584
Admixed American	0.142%	706
South Asian	0.0714%	1,401
Middle Eastern	0.0495%	2,021
East Asian	0.00446%	22,443
European (non-Finnish)	0.00398%	25,107
Finnishnot grpmax-eligible	0.00156%	64,048

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: CHMP4B
Protein: p.Pro186=
Coding: c.558C>T
MANE Select: NM_176812
dbSNP: rs79766928
Type: single nucleotide variant
Location: chr20:33852151 (GRCh38)
Gene constraint: LOEUF 0.208 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 186: the 'disordered' region

Full CHMP4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 31 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CHMP4B p.Gly154Arg Uncertain significance ★★ ⚠ same condition
CHMP4B c.191-5C>T Benign/Likely benign ★★ same condition
CHMP4B p.Gln67Arg Likely pathogenic ★ same condition
CHMP4B p.Glu104Lys Uncertain significance ★ ⚠ same condition
CHMP4B p.Glu161Gln Uncertain significance ★ ⚠ same condition
CHMP4B p.Ser196Ala Uncertain significance ★ ⚠ same condition
CHMP4B c.368+15G>A Likely benign ★ same condition
CHMP4B c.369-15C>T Likely benign ★ 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/chmp4b-p-pro186 (accessed [today's date]).

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