Is CRYAB p.Leu55= (c.165G>A) pathogenic?

CRYAB p.Leu55= (c.165G>A) is classified Benign in CRYAB (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.62%, sas); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Leu55= (c.165G>A)?

CRYAB p.Leu55= (c.165G>A) is associated with Cardiovascular phenotype, cataract 16 multiple types, fatal infantile hypertonic myofibrillar myopathy (ClinVar).

How common is CRYAB p.Leu55= (c.165G>A) in the general population?

CRYAB p.Leu55= (c.165G>A) is low-frequency (popmax 2.62%, sas) (gnomAD).

CRYAB p.Leu55=

c.165G>A · rs2228387 · VCV44233

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.62%, sas)

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 0.26	GERP -0.6, phastCons 0.97
Overall
CADD	9.418	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.62% South Asian · 2,375/90,642 alleles

Filtering AF 2.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5%

Overall 1.85% 29,875/1,612,794 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.62%	38
European (non-Finnish)	2.09%	48
Finnishnot grpmax-eligible	1.55%	65
Remaining individualsnot grpmax-eligible	1.54%	65
Middle Eastern	1.11%	90
Amishnot grpmax-eligible	0.658%	152
Admixed American	0.617%	162
Ashkenazi Jewishnot grpmax-eligible	0.593%	169
African / African-American	0.313%	319
East Asian	0.0134%	7,477

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.Leu55=
Coding: c.165G>A
MANE Select: NM_001289808
dbSNP: rs2228387
Type: single nucleotide variant
Location: chr11:111911560 (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

Cardiovascular phenotype — 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

Similar variants

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 c.-5C>T Uncertain significance ★★ same condition
CRYAB p.Ala168Gly Uncertain significance ★★ ⚠ same condition
CRYAB p.Ala171Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Ala4Thr 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-leu55 (accessed [today's date]).

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