Is CRYBB3 p.Ala2Val (c.5C>T) pathogenic?

CRYBB3 p.Ala2Val (c.5C>T) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1775); Ultra-rare (popmax 0.0361%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Ala2Val (c.5C>T)?

CRYBB3 p.Ala2Val (c.5C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB3 p.Ala2Val (c.5C>T) in the general population?

CRYBB3 p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.0361%, afr) (gnomAD).

What do computational predictors say about CRYBB3 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1775) — an in-silico prediction, not a clinical call.

CRYBB3 p.Ala2Val

c.5C>T · rs751977829 · VCV2385647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1775	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	19.24	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0361% African / African-American · 27/74,854 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00279% 45/1,612,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0361%	2,772
Admixed American	0.00667%	14,989
Remaining individualsnot grpmax-eligible	0.00481%	20,793
European (non-Finnish)	0.000933%	107,215

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_004076
dbSNP: rs751977829
Type: single nucleotide variant
Location: chr22:25201401 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 2: a modified residue (n-acetylalanine; in beta-crystallin b3, n-terminally processed); the 'n-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.Ala2= Benign/Likely benign ★★ same residue
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

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-ala2val (accessed [today's date]).

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