Is CHMP4B p.Arg74Met (c.221G>T) pathogenic?

CHMP4B p.Arg74Met (c.221G>T) is classified Uncertain significance in CHMP4B (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-03). AlphaMissense: likely pathogenic (0.9823); Absent from gnomAD v4.1.

How common is CHMP4B p.Arg74Met (c.221G>T) in the general population?

CHMP4B p.Arg74Met (c.221G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHMP4B p.Arg74Met (c.221G>T)?

AlphaMissense predicts likely pathogenic (score 0.9823) — an in-silico prediction, not a clinical call.

CHMP4B p.Arg74Met

c.221G>T · rs1202549092 · VCV1311838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9823 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9823	likely pathogenic
REVEL	0.553	indeterminate
SaProt	LLR -10.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 41 kb · p 2.1e-18 · regional, not allelic
Overall
CADD	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHMP4B
Protein: p.Arg74Met
Coding: c.221G>T
MANE Select: NM_176812
dbSNP: rs1202549092
Type: single nucleotide variant
Location: chr20:33848497 (GRCh38)
Gene constraint: LOEUF 0.208 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 74: an α-helix

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

Similar variants

CHMP4B p.Gly154Arg Uncertain significance ★★ ⚠ same type
CHMP4B c.190+226C>G Benign ★★ same type
CHMP4B c.191-5C>T Benign/Likely benign ★★ same type
CHMP4B c.610+159T>C Benign ★★ same type
CHMP4B c.610+44A>G Benign ★★ same type
CHMP4B c.610+51C>G Benign ★★ same type
CHMP4B c.610+52T>C Benign ★★ same type
CHMP4B c.610+81G>A Likely benign ★★ 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/chmp4b-p-arg74met (accessed [today's date]).

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