Is CAPZA3 p.Ser248Pro (c.742T>C) pathogenic?

CAPZA3 p.Ser248Pro (c.742T>C) is classified Uncertain significance in CAPZA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: ambiguous (0.3542); Very rare (popmax 0.00223%, eas).

How common is CAPZA3 p.Ser248Pro (c.742T>C) in the general population?

CAPZA3 p.Ser248Pro (c.742T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CAPZA3 p.Ser248Pro (c.742T>C)?

AlphaMissense predicts ambiguous (score 0.3542) — an in-silico prediction, not a clinical call.

CAPZA3 p.Ser248Pro

c.742T>C · VCV3827355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3542	ambiguous
REVEL	0.209	benign-leaning
SaProt	LLR -9.23	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 4.2	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 896 bp · p 0.55 · regional, not allelic
Overall
CADD	24.2	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 0.00223% East Asian · 1/44,862 alleles

Overall 0.000137% 2/1,460,056 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	8.48e-05%	1,179,934

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: CAPZA3
Protein: p.Ser248Pro
Coding: c.742T>C
MANE Select: NM_033328
Type: single nucleotide variant
Location: chr12:18739010 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.01

Full CAPZA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPZA3 p.Ala124Thr Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala153Val Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala219Val Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala226Ser Uncertain significance ★ ⚠ same type
CAPZA3 p.Ala30Gly Uncertain significance ★ ⚠ same type
CAPZA3 p.Arg188Lys Uncertain significance ★ ⚠ same type
CAPZA3 p.Arg257Gln Uncertain significance ★ ⚠ same type
CAPZA3 p.Arg258Ser 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/capza3-p-ser248pro (accessed [today's date]).

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