Is CAPZA3 p.Arg8Ser (c.24G>T) pathogenic?

CAPZA3 p.Arg8Ser (c.24G>T) is classified Uncertain significance in CAPZA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2851); Ultra-rare (popmax 0.0495%, mid).

How common is CAPZA3 p.Arg8Ser (c.24G>T) in the general population?

CAPZA3 p.Arg8Ser (c.24G>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CAPZA3 p.Arg8Ser (c.24G>T)?

AlphaMissense predicts likely benign (score 0.2851) — an in-silico prediction, not a clinical call.

CAPZA3 p.Arg8Ser

c.24G>T · VCV4219035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2851	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.81	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 1.5	GERP 1.5, phastCons 0.9
Regional constraint	o/e 1.03	unconstrained · MANE · 896 bp · p 0.55 · regional, not allelic
Overall
CADD	15.96	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00292% 47/1,611,828 alleles · ultra-rare exomes 42/1,459,648 · genomes 5/152,180 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
Admixed American	0.0217%	4,601
South Asian	0.00331%	30,251
Remaining individualsnot grpmax-eligible	0.00321%	31,195
European (non-Finnish)	0.00221%	45,343

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: CAPZA3
Protein: p.Arg8Ser
Coding: c.24G>T
MANE Select: NM_033328
Type: single nucleotide variant
Location: chr12:18738292 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.01

Full CAPZA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPZA3 p.Arg8Met Uncertain significance ★ ⚠ same residue
CAPZA3 p.Ala124Thr Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala153Val Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala219Val Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala226Ser Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala30Gly Uncertain significance ★ ⚠ same type
CAPZA3 p.Arg188Lys Uncertain significance ★ ⚠ same type
CAPZA3 p.Arg257Gln 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/capza3-p-arg8ser (accessed [today's date]).

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