Is CRYAB p.Pro39Ala (c.115C>G) pathogenic?

CRYAB p.Pro39Ala (c.115C>G) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1117); Very rare (popmax 0.00763%, nfe); Associated with myofibrillar myopathy 2.

What condition is associated with CRYAB p.Pro39Ala (c.115C>G)?

CRYAB p.Pro39Ala (c.115C>G) is associated with myofibrillar myopathy 2, cataract 16 multiple types, fatal infantile hypertonic myofibrillar myopathy (ClinVar).

How common is CRYAB p.Pro39Ala (c.115C>G) in the general population?

CRYAB p.Pro39Ala (c.115C>G) is very rare (popmax 0.00763%, nfe) (gnomAD).

How is Alpha-B crystallin-related late-onset myopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYAB p.Pro39Ala (c.115C>G)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

CRYAB p.Pro39Ala

c.115C>G · rs145768025 · VCV571646

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

myofibrillar myopathy 2

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.12, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	19.39	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00763% European (non-Finnish) · 90/1,179,722 alleles

Filtering AF 0.00631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00584%

Overall 0.00558% 90/1,612,966 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.Pro39Ala
Coding: c.115C>G
MANE Select: NM_001289808
dbSNP: rs145768025
Type: single nucleotide variant
Location: chr11:111911610 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB

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

Disease context

myofibrillar myopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 16 multiple types fatal infantile hypertonic myofibrillar myopathy dilated cardiomyopathy 1II

For Alpha-B crystallin-related late-onset myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CRYAB p.Pro39Gln Uncertain significance ★★ ⚠ same residue
CRYAB p.Pro39Ser Uncertain significance ★★ ⚠ same residue
CRYAB p.Pro39= Likely benign ★★ same residue
CRYAB p.Pro39Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same condition
CRYAB c.324+5G>T Uncertain significance ★★ same condition
CRYAB c.325-1G>A Uncertain significance ★★ same condition
CRYAB c.325-2A>G 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-pro39ala (accessed [today's date]).

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