Is CAPZA2 p.Thr180Ile (c.539C>T) pathogenic?

CAPZA2 p.Thr180Ile (c.539C>T) is classified Uncertain significance in CAPZA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2212); Very rare (popmax 8.55e-05%, nfe).

How common is CAPZA2 p.Thr180Ile (c.539C>T) in the general population?

CAPZA2 p.Thr180Ile (c.539C>T) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

What do computational predictors say about CAPZA2 p.Thr180Ile (c.539C>T)?

AlphaMissense predicts likely benign (score 0.2212) — an in-silico prediction, not a clinical call.

CAPZA2 p.Thr180Ile

c.539C>T · VCV4648231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2212	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 55 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	25.0	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 8.55e-05% European (non-Finnish) · 1/1,169,352 alleles

Overall 0.000657% 1/152,116 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.Thr180Ile
Coding: c.539C>T
MANE Select: NM_006136
Type: single nucleotide variant
Location: chr7:116910265 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 93.11

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

Similar variants

CAPZA2 p.Thr180Ser Uncertain significance ★ ⚠ same residue
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

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-thr180ile (accessed [today's date]).

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