Is CAPZB p.Ser34Cys (c.100A>T) pathogenic?

CAPZB p.Ser34Cys (c.100A>T) is classified Uncertain significance in CAPZB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.0961); Ultra-rare (popmax 0.011%, sas).

How common is CAPZB p.Ser34Cys (c.100A>T) in the general population?

CAPZB p.Ser34Cys (c.100A>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CAPZB p.Ser34Cys (c.100A>T)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

CAPZB p.Ser34Cys

c.100A>T · VCV4219042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -10.52	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 146 kb · p 2.7e-21 · regional, not allelic
Overall
CADD	23.9	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 0.011% South Asian · 10/91,086 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000991% 16/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,109
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00223%	44,882

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: CAPZB
Protein: p.Ser34Cys
Coding: c.100A>T
MANE Select: NM_004930
Type: single nucleotide variant
Location: chr1:19385620 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.18 · 8 PDB
Residue 34: an α-helix

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

Similar variants

CAPZB c.731+1496C>G Uncertain significance ★ ⚠ same type
CAPZB c.731+1519C>A Uncertain significance ★ same type
CAPZB c.731+1520A>G Uncertain significance ★ ⚠ same type
CAPZB c.731+1568G>A Uncertain significance ★ same type
CAPZB p.Arg215His Uncertain significance ★ ⚠ same type
CAPZB p.Cys147Ser Uncertain significance ★ ⚠ same type
CAPZB p.Met88Val Uncertain significance ★ ⚠ same type
CAPZB p.Thr164Ile 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/capzb-p-ser34cys (accessed [today's date]).

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