Is CAPZA2 p.Ala2Thr (c.4G>A) pathogenic?

CAPZA2 p.Ala2Thr (c.4G>A) is classified Uncertain significance in CAPZA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: ambiguous (0.4824); Very rare (popmax 8.76e-05%, nfe).

How common is CAPZA2 p.Ala2Thr (c.4G>A) in the general population?

CAPZA2 p.Ala2Thr (c.4G>A) is very rare (popmax 8.76e-05%, nfe) (gnomAD).

What do computational predictors say about CAPZA2 p.Ala2Thr (c.4G>A)?

AlphaMissense predicts ambiguous (score 0.4824) — an in-silico prediction, not a clinical call.

CAPZA2 p.Ala2Thr

c.4G>A · rs2485956153 · VCV3027222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.76e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4824	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -7.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 55 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	24.4	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 8.76e-05% European (non-Finnish) · 1/1,142,012 alleles

Overall 7.21e-05% 1/1,387,198 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: CAPZA2
Protein: p.Ala2Thr
Coding: c.4G>A
MANE Select: NM_006136
dbSNP: rs2485956153
Type: single nucleotide variant
Location: chr7:116862615 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 93.11
Residue 2: a modified residue (n-acetylalanine)

Full CAPZA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPZA2 p.Arg259Cys Likely pathogenic ★ same type
CAPZA2 p.Lys256Glu Pathogenic ★ same type
CAPZA2 c.103+1G>A Uncertain significance ★ same type
CAPZA2 c.585+1G>T Uncertain significance ★ same type
CAPZA2 c.585+2T>G Uncertain significance ★ same type
CAPZA2 c.720+1G>A Uncertain significance ★ same type
CAPZA2 p.Ala116Thr Uncertain significance ★ ⚠ same type
CAPZA2 p.Ala130Val 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/capza2-p-ala2thr (accessed [today's date]).

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