Is CCZ1B p.Arg446Gln (c.1337G>A) pathogenic?

CCZ1B p.Arg446Gln (c.1337G>A) is classified Likely benign in CCZ1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0561); Very rare (popmax 0.00959%, afr).

How common is CCZ1B p.Arg446Gln (c.1337G>A) in the general population?

CCZ1B p.Arg446Gln (c.1337G>A) is very rare (popmax 0.00959%, afr) (gnomAD).

What do computational predictors say about CCZ1B p.Arg446Gln (c.1337G>A)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

CCZ1B p.Arg446Gln

c.1337G>A · VCV3997926

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00959%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 14 kb · p 3.9e-31 · regional, not allelic
Overall
CADD	19.95	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 0.00959% African / African-American · 5/52,122 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00242% 29/1,199,508 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00959%	10,424
European (non-Finnish)	0.00254%	39,370
Remaining individualsnot grpmax-eligible	0.00213%	46,992

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: CCZ1B
Protein: p.Arg446Gln
Coding: c.1337G>A
MANE Select: NM_198097
Type: single nucleotide variant
Location: chr7:6801004 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.86 · 1 PDB

Full CCZ1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCZ1B p.Ala14Pro Uncertain significance ★ ⚠ same type
CCZ1B p.Ala155Gly Uncertain significance ★ ⚠ same type
CCZ1B p.Ala294Thr Uncertain significance ★ ⚠ same type
CCZ1B p.Ala323Asp Uncertain significance ★ ⚠ same type
CCZ1B p.Ala323Thr Conflicting classifications of pathogenicity ★ ⚠ same type
CCZ1B p.Ala330Gly Uncertain significance ★ ⚠ same type
CCZ1B p.Ala4Thr Uncertain significance ★ ⚠ same type
CCZ1B p.Ala8Thr 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/ccz1b-p-arg446gln (accessed [today's date]).

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