Is CRYBB3 p.Phe208Leu (c.622T>C) pathogenic?

CRYBB3 p.Phe208Leu (c.622T>C) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-29). AlphaMissense: likely pathogenic (0.9095); Very rare (popmax 0.000848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Phe208Leu (c.622T>C)?

CRYBB3 p.Phe208Leu (c.622T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB3 p.Phe208Leu (c.622T>C) in the general population?

CRYBB3 p.Phe208Leu (c.622T>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about CRYBB3 p.Phe208Leu (c.622T>C)?

AlphaMissense predicts likely pathogenic (score 0.9095) — an in-silico prediction, not a clinical call.

CRYBB3 p.Phe208Leu

c.622T>C · rs377319643 · VCV3077715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9095	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	25.1	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 0.000848% European (non-Finnish) · 10/1,179,536 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000685% 10/1,460,478 alleles · very 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: CRYBB3
Protein: p.Phe208Leu
Coding: c.622T>C
MANE Select: NM_004076
dbSNP: rs377319643
Type: single nucleotide variant
Location: chr22:25207198 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 208: the 'c-terminal arm' region

Full CRYBB3 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

CRYBB3 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg127His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg152Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg196His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Leu Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Asp110Gly Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Ala13Gly Conflicting classifications of pathogenicity ★ ⚠ 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/crybb3-p-phe208leu (accessed [today's date]).

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