Is CGB2 p.Ser145Arg (c.435C>A) pathogenic?

CGB2 p.Ser145Arg (c.435C>A) is classified Uncertain significance in CGB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.2861); Very rare (popmax 0.00223%, eas).

How common is CGB2 p.Ser145Arg (c.435C>A) in the general population?

CGB2 p.Ser145Arg (c.435C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CGB2 p.Ser145Arg (c.435C>A)?

AlphaMissense predicts likely benign (score 0.2861) — an in-silico prediction, not a clinical call.

CGB2 p.Ser145Arg

c.435C>A · VCV3491725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2861	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69
Regional constraint	o/e 0.94	unconstrained · MANE · 68 bp · p 0.75 · regional, not allelic
Overall
CADD	12.52	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 0.00223% East Asian · 1/44,878 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000931% 15/1,610,940 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,004
Remaining individualsnot grpmax-eligible	0.00321%	31,142
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.000339%	294,961

Finnish 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: CGB2
Protein: p.Ser145Arg
Coding: c.435C>A
MANE Select: NM_033378
Type: single nucleotide variant
Location: chr19:49033164 (GRCh38)
Gene constraint: LOEUF 1.73 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.22
Residue 145: the 'disordered' region

Full CGB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CGB2 p.Ala135Asp Benign ★★ same type
CGB2 p.Ala141Gly Uncertain significance ★ ⚠ same type
CGB2 p.Arg113Cys Uncertain significance ★ ⚠ same type
CGB2 p.Arg24Gln Uncertain significance ★ ⚠ same type
CGB2 p.Arg26Gln Uncertain significance ★ ⚠ same type
CGB2 p.Arg26Trp Uncertain significance ★ ⚠ same type
CGB2 p.Arg78Gly Uncertain significance ★ ⚠ same type
CGB2 p.Arg81His 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/cgb2-p-ser145arg (accessed [today's date]).

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