Is CRYBA2 p.Ala80Thr (c.238G>A) pathogenic?

CRYBA2 p.Ala80Thr (c.238G>A) is classified Uncertain significance in CRYBA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). AlphaMissense: likely benign (0.1711); Ultra-rare (popmax 0.0312%, eas); Associated with CRYBA2-related disorder.

What condition is associated with CRYBA2 p.Ala80Thr (c.238G>A)?

CRYBA2 p.Ala80Thr (c.238G>A) is associated with CRYBA2-related disorder (ClinVar).

How common is CRYBA2 p.Ala80Thr (c.238G>A) in the general population?

CRYBA2 p.Ala80Thr (c.238G>A) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about CRYBA2 p.Ala80Thr (c.238G>A)?

AlphaMissense predicts likely benign (score 0.1711) — an in-silico prediction, not a clinical call.

CRYBA2 p.Ala80Thr

c.238G>A · rs200129430 · VCV2454415

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CRYBA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1711	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.99, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,921 bp · p 0.71 · regional, not allelic
Overall
CADD	22.6	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 0.0312% East Asian · 14/44,878 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0212%

Overall 0.0206% 332/1,613,338 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
East Asiangrpmax	0.0312%	3,206
European (non-Finnish)	0.0244%	4,097
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
Remaining individualsnot grpmax-eligible	0.0144%	6,941
Admixed American	0.00667%	15,001
African / African-American	0.004%	24,972
South Asian	0.0011%	91,084

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CRYBA2
Protein: p.Ala80Thr
Coding: c.238G>A
MANE Select: NM_057093
dbSNP: rs200129430
Type: single nucleotide variant
Location: chr2:218992167 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12
Residue 80: the beta/gamma crystallin 'greek key' 2 domain

Full CRYBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CRYBA2-related disorder

Similar variants

CRYBA2 p.Arg107His Uncertain significance ★ ⚠ same condition
CRYBA2 p.Cys27Ter Uncertain significance same condition
CRYBA2 p.Arg169Gln Benign same condition
CRYBA2 c.303+127A>G Benign ★★ same type
CRYBA2 c.304-16T>C Benign ★★ same type
CRYBA2 c.303+5G>A Uncertain significance ★ same type
CRYBA2 c.446+1G>A Uncertain significance ★ same type
CRYBA2 p.Ala10Pro Uncertain significance ★ ⚠ same type

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/cryba2-p-ala80thr (accessed [today's date]).

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