Is CRYAB p.Met1Ile (c.3G>A) pathogenic?

CRYAB p.Met1Ile (c.3G>A) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-18). Ultra-rare (popmax 0.0572%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Met1Ile (c.3G>A)?

CRYAB p.Met1Ile (c.3G>A) is associated with Cardiovascular phenotype, cardiomyopathy, cataract 16 multiple types (ClinVar).

How common is CRYAB p.Met1Ile (c.3G>A) in the general population?

CRYAB p.Met1Ile (c.3G>A) is ultra-rare (popmax 0.0572%, eas) (gnomAD).

CRYAB p.Met1Ile

c.3G>A · rs397516686 · VCV44236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0572%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.822	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0572% East Asian · 25/43,710 alleles

Filtering AF 0.0397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.00158% 25/1,581,302 alleles · ultra-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.Met1Ile
Coding: c.3G>A
MANE Select: NM_001289808
dbSNP: rs397516686
Type: single nucleotide variant
Location: chr11:111911722 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 1: a modified residue (n-acetylmethionine)

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

Similar variants

CRYAB p.Met1Thr 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
CRYAB c.-5C>T 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-met1ile (accessed [today's date]).

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