Is CCZ1B p.Ala14Pro (c.40G>C) pathogenic?

CCZ1B p.Ala14Pro (c.40G>C) is classified Uncertain significance in CCZ1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0979); Very rare (popmax 0.00073%, nfe).

How common is CCZ1B p.Ala14Pro (c.40G>C) in the general population?

CCZ1B p.Ala14Pro (c.40G>C) is very rare (popmax 0.00073%, nfe) (gnomAD).

What do computational predictors say about CCZ1B p.Ala14Pro (c.40G>C)?

AlphaMissense predicts likely benign (score 0.0979) — an in-silico prediction, not a clinical call.

CCZ1B p.Ala14Pro

c.40G>C · VCV4650365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00073%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0979	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.75	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 -1	phastCons 0.003
Regional constraint	o/e 0.23	constrained · MANE · 1,715 bp · p 2.7e-13 · regional, not allelic
Overall
CADD	13.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00073% European (non-Finnish) · 3/411,186 alleles

Filtering AF 0.000194% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000603% 3/497,800 alleles · very rare

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.Ala14Pro
Coding: c.40G>C
MANE Select: NM_198097
Type: single nucleotide variant
Location: chr7:6826158 (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.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
CCZ1B p.Arg107Gln 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-ala14pro (accessed [today's date]).

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