Is CRYAB p.Gly154Ser (c.460G>A) pathogenic?

CRYAB p.Gly154Ser (c.460G>A) is classified Conflicting classifications of pathogenicity in CRYAB (ClinVar, Conflicting submitters, 22 submitters; last evaluated 2026-07-29). AlphaMissense: likely benign (0.0736); Rare (popmax 0.15%, nfe); Associated with hypertrophic cardiomyopathy.

What condition is associated with CRYAB p.Gly154Ser (c.460G>A)?

CRYAB p.Gly154Ser (c.460G>A) is associated with hypertrophic cardiomyopathy, cardiomyopathy, congestive heart failure (ClinVar).

How common is CRYAB p.Gly154Ser (c.460G>A) in the general population?

CRYAB p.Gly154Ser (c.460G>A) is rare (popmax 0.15%, nfe) (gnomAD).

What do computational predictors say about CRYAB p.Gly154Ser (c.460G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

CRYAB p.Gly154Ser

c.460G>A · rs150516929 · VCV41926

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.507	indeterminate
SaProt	LLR -5.17	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 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,623 bp · p 0.098 · regional, not allelic
Overall
CADD	19.93	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 0.15% European (non-Finnish) · 1,765/1,180,016 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.141%

Overall 0.119% 1,913/1,613,842 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.15%	669
Finnishnot grpmax-eligible	0.103%	970
Remaining individualsnot grpmax-eligible	0.072%	1,388
Admixed American	0.0416%	2,401
Middle Eastern	0.0172%	5,820
African / African-American	0.0133%	7,502
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Gly154Ser
Coding: c.460G>A
MANE Select: NM_001289808
dbSNP: rs150516929
Type: single nucleotide variant
Location: chr11:111908832 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 21 PDB
Residue 154: the shsp domain; the 'disordered' region; a UniProt-annotated variant site (in cmd1ii and mfm2a; uncertain significance)

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

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CRYAB p.Gly154Asp Uncertain significance ★ ⚠ same residue
CRYAB p.Gly154= 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-gly154ser (accessed [today's date]).

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