Is CAPZA3 p.Arg258Ser (c.774G>C) pathogenic?

CAPZA3 p.Arg258Ser (c.774G>C) is classified Uncertain significance in CAPZA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9902); Ultra-rare (popmax 0.017%, nfe).

How common is CAPZA3 p.Arg258Ser (c.774G>C) in the general population?

CAPZA3 p.Arg258Ser (c.774G>C) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about CAPZA3 p.Arg258Ser (c.774G>C)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

CAPZA3 p.Arg258Ser

c.774G>C · rs139395998 · VCV2588627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 1% in CAPZA3
REVEL	0.503	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -3.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 896 bp · p 0.55 · regional, not allelic
Overall
CADD	21.5	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 0.017% European (non-Finnish) · 201/1,179,914 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0148% 238/1,611,786 alleles · ultra-rare exomes 214/1,459,710 · genomes 24/152,076 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
Finnishnot grpmax-eligible	0.029%	3,446
European (non-Finnish)grpmax	0.017%	5,870
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,924
Admixed American	0.00167%	59,944

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg258Ser
Coding: c.774G>C
MANE Select: NM_033328
dbSNP: rs139395998
Type: single nucleotide variant
Location: chr12:18739042 (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.Arg264Leu 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-arg258ser (accessed [today's date]).

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