Is CAPZA2 p.Arg259Leu (c.776G>T) pathogenic?

CAPZA2 p.Arg259Leu (c.776G>T) is classified Conflicting classifications of pathogenicity in CAPZA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-02-16). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with CAPZA2 p.Arg259Leu (c.776G>T)?

CAPZA2 p.Arg259Leu (c.776G>T) is associated with intellectual disability (ClinVar).

How common is CAPZA2 p.Arg259Leu (c.776G>T) in the general population?

CAPZA2 p.Arg259Leu (c.776G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPZA2 p.Arg259Leu (c.776G>T)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

CAPZA2 p.Arg259Leu

c.776G>T · rs1791701248 · VCV830216

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 5% in CAPZA2
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -14.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 55 kb · p 2.8e-07 · regional, not allelic
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPZA2
Protein: p.Arg259Leu
Coding: c.776G>T
MANE Select: NM_006136
dbSNP: rs1791701248
Type: single nucleotide variant
Location: chr7:116917782 (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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPZA2 p.Arg259Cys Likely pathogenic ★ same residue
CAPZA2 p.Lys256Glu Pathogenic ★ same condition
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-arg259leu (accessed [today's date]).

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