Is CRYAB p.Thr63= (c.189T>C) pathogenic?

CRYAB p.Thr63= (c.189T>C) is classified Likely benign in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). Very rare (popmax 0.000594%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Thr63= (c.189T>C)?

CRYAB p.Thr63= (c.189T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CRYAB p.Thr63= (c.189T>C) in the general population?

CRYAB p.Thr63= (c.189T>C) is very rare (popmax 0.000594%, nfe) (gnomAD).

CRYAB p.Thr63=

c.189T>C · VCV4007139

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.039	GERP -1.2, phastCons 0.046
Overall
CADD	8.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,179,018 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00048% 7/1,458,796 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: CRYAB
Protein: p.Thr63=
Coding: c.189T>C
MANE Select: NM_001289808
Type: single nucleotide variant
Location: chr11:111911536 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 63: the shsp domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYAB p.Thr63Ala Uncertain significance ★★ ⚠ same residue
CRYAB p.Thr63Asn Uncertain significance ★ ⚠ same residue
CRYAB p.Thr63Ile Uncertain significance ★ ⚠ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same condition
CRYAB c.325-2A>G Uncertain significance ★★ same condition
CRYAB c.-5C>T Uncertain significance ★★ same condition
CRYAB p.Ala171Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg11Cys Uncertain significance ★★ ⚠ same condition

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/cryab-p-thr63 (accessed [today's date]).

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