Is CRYAB p.Arg50Pro (c.149G>C) pathogenic?

CRYAB p.Arg50Pro (c.149G>C) is classified Uncertain significance in CRYAB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-06). AlphaMissense: ambiguous (0.4412); Very rare (popmax 6.2e-05%); Associated with Cardiovascular phenotype.

What condition is associated with CRYAB p.Arg50Pro (c.149G>C)?

CRYAB p.Arg50Pro (c.149G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CRYAB p.Arg50Pro (c.149G>C) in the general population?

CRYAB p.Arg50Pro (c.149G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about CRYAB p.Arg50Pro (c.149G>C)?

AlphaMissense predicts ambiguous (score 0.4412) — an in-silico prediction, not a clinical call.

CRYAB p.Arg50Pro

c.149G>C · VCV4869431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4412 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4412	ambiguous
REVEL	0.672	pathogenic-leaning
SaProt	LLR -9.13	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,286 bp · p 0.3 · regional, not allelic
Overall
CADD	25.2	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 6.2e-05%

Overall 6.2e-05% 1/1,613,040 alleles · very rare exomes 1/1,460,974 · genomes 0/152,066 · joint denominator

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.Arg50Pro
Coding: c.149G>C
MANE Select: NM_001289808
Type: single nucleotide variant
Location: chr11:111911576 (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

Similar variants

CRYAB p.Arg50Gln Uncertain significance ★★ ⚠ same residue
CRYAB p.Arg50Trp Uncertain significance ★★ ⚠ same residue
CRYAB c.324+4T>A Uncertain significance ★★ same condition
CRYAB c.325-2A>G Uncertain significance ★★ same condition
CRYAB c.-5C>T Uncertain significance ★★ same condition
CRYAB p.Ala171Thr Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg11Cys Uncertain significance ★★ ⚠ same condition
CRYAB p.Arg123Gln 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-arg50pro (accessed [today's date]).

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