Is CAPZA1 p.Ile16Val (c.46A>G) pathogenic?

CAPZA1 p.Ile16Val (c.46A>G) is classified Uncertain significance in CAPZA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1472); Ultra-rare (popmax 0.0129%, nfe).

How common is CAPZA1 p.Ile16Val (c.46A>G) in the general population?

CAPZA1 p.Ile16Val (c.46A>G) is ultra-rare (popmax 0.0129%, nfe) (gnomAD).

What do computational predictors say about CAPZA1 p.Ile16Val (c.46A>G)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

CAPZA1 p.Ile16Val

c.46A>G · rs369340611 · VCV2205575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -10.35	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 34 kb · p 0.33 · regional, not allelic
Overall
CADD	24.0	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 0.0129% European (non-Finnish) · 145/1,124,600 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.0103% 157/1,523,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0129%	7,756
African / African-American	0.00547%	18,267
South Asian	0.00528%	18,943
Finnishnot grpmax-eligible	0.00496%	20,156
Remaining individualsnot grpmax-eligible	0.00173%	57,966

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.Ile16Val
Coding: c.46A>G
MANE Select: NM_006135
dbSNP: rs369340611
Type: single nucleotide variant
Location: chr1:112647216 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 93.19 · 10 PDB
Residue 16: an α-helix

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.Ala50Ser 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

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-ile16val (accessed [today's date]).

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