Is CRYGB p.Ser78Pro (c.232T>C) pathogenic?

CRYGB p.Ser78Pro (c.232T>C) is classified Uncertain significance in CRYGB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely pathogenic (0.952); Ultra-rare (popmax 0.0183%, amr); Associated with cataract 39 multiple types.

What condition is associated with CRYGB p.Ser78Pro (c.232T>C)?

CRYGB p.Ser78Pro (c.232T>C) is associated with cataract 39 multiple types (ClinVar).

How common is CRYGB p.Ser78Pro (c.232T>C) in the general population?

CRYGB p.Ser78Pro (c.232T>C) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYGB p.Ser78Pro (c.232T>C)?

AlphaMissense predicts likely pathogenic (score 0.952) — an in-silico prediction, not a clinical call.

CRYGB p.Ser78Pro

c.232T>C · VCV3641487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 39 multiple types

Computational evidence

Protein change
AlphaMissense	0.952	likely pathogenic · top 7% in CRYGB
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,479 bp · p 0.091 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0183% Admixed American · 11/59,970 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.000806% 13/1,613,284 alleles · ultra-rare exomes 10/1,461,374 · genomes 3/151,910 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,452
Remaining individualsnot grpmax-eligible	0.0016%	62,442
African / African-American	0.00134%	74,802

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: CRYGB
Protein: p.Ser78Pro
Coding: c.232T>C
MANE Select: NM_005210
Type: single nucleotide variant
Location: chr2:208145794 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.86 · 2 PDB
Residue 78: a β-strand; the beta/gamma crystallin 'greek key' 2 domain

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

Disease context

cataract 39 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CRYGB p.Ala160Pro Uncertain significance ★★ ⚠ same condition
CRYGB p.Arg116His Uncertain significance ★★ ⚠ same condition
CRYGB p.Asp95Asn Uncertain significance ★★ ⚠ same condition
CRYGB p.Ile82Val Uncertain significance ★★ ⚠ same condition
CRYGB p.Pro84Leu Uncertain significance ★★ ⚠ same condition
CRYGB p.Ser16Asn Uncertain significance ★★ ⚠ same condition
CRYGB p.Arg59Trp Benign ★★ same condition
CRYGB p.Ile111Leu Benign ★★ 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/crygb-p-ser78pro (accessed [today's date]).

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