Is CRYAB p.Leu89His (c.266T>A) pathogenic?

CRYAB p.Leu89His (c.266T>A) is classified Uncertain significance in CRYAB (ClinVar, No assertion criteria, 2 submitters). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1.

How common is CRYAB p.Leu89His (c.266T>A) in the general population?

CRYAB p.Leu89His (c.266T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYAB p.Leu89His (c.266T>A)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CRYAB p.Leu89His

c.266T>A · rs2137381932 · VCV1297734

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 2% in CRYAB
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -17.62	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,623 bp · p 0.098 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: CRYAB
Protein: p.Leu89His
Coding: c.266T>A
MANE Select: NM_001289808
dbSNP: rs2137381932
Type: single nucleotide variant
Location: chr11:111910385 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 89: the shsp domain; a β-strand

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

Similar variants

CRYAB p.Leu89Phe Uncertain significance ★ ⚠ same residue
CRYAB p.Leu89= Likely benign ★ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same type
CRYAB c.324+5G>T Uncertain significance ★★ same type
CRYAB c.325-1G>A Uncertain significance ★★ same type
CRYAB c.325-2A>G Uncertain significance ★★ same type
CRYAB c.-5C>T Uncertain significance ★★ same type
CRYAB p.Ala168Gly 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/cryab-p-leu89his (accessed [today's date]).

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