Is CRYBB2 p.Phe177Leu (c.529T>C) pathogenic?

CRYBB2 p.Phe177Leu (c.529T>C) is classified Uncertain significance in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-21). AlphaMissense: likely pathogenic (0.9623); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CRYBB2 p.Phe177Leu (c.529T>C)?

CRYBB2 p.Phe177Leu (c.529T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB2 p.Phe177Leu (c.529T>C) in the general population?

CRYBB2 p.Phe177Leu (c.529T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYBB2 p.Phe177Leu (c.529T>C)?

AlphaMissense predicts likely pathogenic (score 0.9623) — an in-silico prediction, not a clinical call.

CRYBB2 p.Phe177Leu

c.529T>C · VCV4869436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9623 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9623	likely pathogenic
REVEL	0.637	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.36, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRYBB2
Protein: p.Phe177Leu
Coding: c.529T>C
MANE Select: NM_000496
Type: single nucleotide variant
Location: chr22:25231683 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 177: a UniProt-annotated variant site (in ctrct3); an α-helix; the beta/gamma crystallin 'greek key' 4 domain

Full CRYBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYBB2 p.Ala9Val Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Ala134Thr Uncertain significance ★ ⚠ same condition
CRYBB2 p.Arg189His Uncertain significance ★ ⚠ same condition
CRYBB2 p.Asn40Ser Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gln105Lys Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Asp Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Val 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/crybb2-p-phe177leu (accessed [today's date]).

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