Is CRYAB p.Arg157His (c.470G>A) pathogenic?

CRYAB p.Arg157His (c.470G>A) is classified Uncertain significance in CRYAB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-27). AlphaMissense: likely benign (0.3069); Ultra-rare (popmax 0.0758%, eas); Associated with myofibrillar myopathy 2.

What condition is associated with CRYAB p.Arg157His (c.470G>A)?

CRYAB p.Arg157His (c.470G>A) is associated with myofibrillar myopathy 2, cataract 16 multiple types, fatal infantile hypertonic myofibrillar myopathy (ClinVar).

How common is CRYAB p.Arg157His (c.470G>A) in the general population?

CRYAB p.Arg157His (c.470G>A) is ultra-rare (popmax 0.0758%, eas) (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.Arg157His (c.470G>A)?

AlphaMissense predicts likely benign (score 0.3069) — an in-silico prediction, not a clinical call.

CRYAB p.Arg157His

c.470G>A · rs141638421 · VCV41925

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0758%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myofibrillar myopathy 2

Computational evidence

Protein change
AlphaMissense	0.3069	likely benign
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,623 bp · p 0.098 · regional, not allelic
Overall
CADD	32.0	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 0.0758% East Asian · 34/44,878 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.00775% 125/1,613,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0758%	1,320
European (non-Finnish)	0.00678%	14,750
Admixed American	0.00667%	15,004
African / African-American	0.00533%	18,757
Remaining individualsnot grpmax-eligible	0.0032%	31,232
South Asian	0.0011%	91,062

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.Arg157His
Coding: c.470G>A
MANE Select: NM_001289808
dbSNP: rs141638421
Type: single nucleotide variant
Location: chr11:111908822 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 157: the shsp domain; the 'disordered' region; a UniProt-annotated variant site (in cmd1ii); a β-strand

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.Arg157Cys Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg157= Likely benign ★★ 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
CRYAB p.Ala168Gly Uncertain significance ★★ ⚠ same condition
CRYAB p.Ala171Thr 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-arg157his (accessed [today's date]).

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