Is CRYBB2 p.Asn35Ser (c.104A>G) pathogenic?

CRYBB2 p.Asn35Ser (c.104A>G) is classified Likely benign in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.0498); Ultra-rare (popmax 0.0264%, sas); Associated with Inborn genetic diseases.

What condition is associated with CRYBB2 p.Asn35Ser (c.104A>G)?

CRYBB2 p.Asn35Ser (c.104A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB2 p.Asn35Ser (c.104A>G) in the general population?

CRYBB2 p.Asn35Ser (c.104A>G) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about CRYBB2 p.Asn35Ser (c.104A>G)?

AlphaMissense predicts likely benign (score 0.0498) — an in-silico prediction, not a clinical call.

CRYBB2 p.Asn35Ser

c.104A>G · VCV4007157

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0498	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -4.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.92	GERP -3.1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	0.514	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 0.0264% South Asian · 24/91,058 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00366% 59/1,613,474 alleles · ultra-rare exomes 58/1,461,184 · genomes 1/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,794
African / African-American	0.00666%	15,007
European (non-Finnish)	0.00246%	40,669
Admixed American	0.00167%	60,024

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: CRYBB2
Protein: p.Asn35Ser
Coding: c.104A>G
MANE Select: NM_000496
Type: single nucleotide variant
Location: chr22:25224967 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 35: a β-strand; the beta/gamma crystallin 'greek key' 1 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-asn35ser (accessed [today's date]).

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