Is CHMP4B p.Phe42= (c.126C>T) pathogenic?

CHMP4B p.Phe42= (c.126C>T) is classified Likely benign in CHMP4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Very rare (popmax 0.00334%, amr); Associated with cataract 31 multiple types.

What condition is associated with CHMP4B p.Phe42= (c.126C>T)?

CHMP4B p.Phe42= (c.126C>T) is associated with cataract 31 multiple types (ClinVar).

How common is CHMP4B p.Phe42= (c.126C>T) in the general population?

CHMP4B p.Phe42= (c.126C>T) is very rare (popmax 0.00334%, amr) (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.Phe42=

c.126C>T · VCV4746511

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

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 -0.004	GERP -1.9, phastCons 0.41
Overall
CADD	11.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,964 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00223% 36/1,613,838 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed Americangrpmax	0.00334%	29,982
European (non-Finnish)	0.00237%	42,142
South Asian	0.0022%	45,528
African / African-American	0.00133%	74,938

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: CHMP4B
Protein: p.Phe42=
Coding: c.126C>T
MANE Select: NM_176812
Type: single nucleotide variant
Location: chr20:33811594 (GRCh38)
Gene constraint: LOEUF 0.208 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 42: an α-helix

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.Pro186= 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

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-phe42 (accessed [today's date]).

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