Is CAPZA1 p.Ala50Ser (c.148G>T) pathogenic?

CAPZA1 p.Ala50Ser (c.148G>T) is classified Uncertain significance in CAPZA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.718); Very rare (popmax 0.00134%, afr).

How common is CAPZA1 p.Ala50Ser (c.148G>T) in the general population?

CAPZA1 p.Ala50Ser (c.148G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CAPZA1 p.Ala50Ser (c.148G>T)?

AlphaMissense predicts likely pathogenic (score 0.718) — an in-silico prediction, not a clinical call.

CAPZA1 p.Ala50Ser

c.148G>T · VCV4219024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.718	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 34 kb · p 0.33 · regional, not allelic
Overall
CADD	25.9	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 0.00134% African / African-American · 1/74,906 alleles

Overall 6.86e-05% 1/1,458,398 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: CAPZA1
Protein: p.Ala50Ser
Coding: c.148G>T
MANE Select: NM_006135
Type: single nucleotide variant
Location: chr1:112649462 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 93.19 · 10 PDB
Residue 50: a β-strand

Full CAPZA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPZA1 c.506+1G>C Uncertain significance ★ same type
CAPZA1 p.Arg15Cys Uncertain significance ★ same type
CAPZA1 p.Arg172His Uncertain significance ★ ⚠ same type
CAPZA1 p.Asn138Ser Uncertain significance ★ ⚠ same type
CAPZA1 p.Asn34Ser Uncertain significance ★ ⚠ same type
CAPZA1 p.Asp10Ala Uncertain significance ★ ⚠ same type
CAPZA1 p.Asp211Glu Uncertain significance ★ ⚠ same type
CAPZA1 p.Asp214His 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/capza1-p-ala50ser (accessed [today's date]).

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