Is CPEB3 p.Pro166Arg (c.497C>G) pathogenic?

CPEB3 p.Pro166Arg (c.497C>G) is classified Uncertain significance in CPEB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely benign (0.2315); Very rare (popmax 0.00682%, nfe).

How common is CPEB3 p.Pro166Arg (c.497C>G) in the general population?

CPEB3 p.Pro166Arg (c.497C>G) is very rare (popmax 0.00682%, nfe) (gnomAD).

What do computational predictors say about CPEB3 p.Pro166Arg (c.497C>G)?

AlphaMissense predicts likely benign (score 0.2315) — an in-silico prediction, not a clinical call.

CPEB3 p.Pro166Arg

c.497C>G · VCV3835874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00682%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2315	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -9.95	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 6.4	GERP 0.027, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 129 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.3	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 0.00682% European (non-Finnish) · 78/1,143,802 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00513%

Overall 0.0052% 80/1,537,052 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00682%	14,664
Remaining individualsnot grpmax-eligible	0.0017%	58,906
African / African-American	0.00142%	70,514

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: CPEB3
Protein: p.Pro166Arg
Coding: c.497C>G
MANE Select: NM_014912
Type: single nucleotide variant
Location: chr10:92239854 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 6 PDB
Residue 166: the 'disordered' region

Full CPEB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPEB3 p.Pro166Ser Uncertain significance ★ same residue
CPEB3 p.Val280= Benign ★★ same type
CPEB3 p.Ala101Ser Uncertain significance ★ ⚠ same type
CPEB3 p.Ala118Thr Uncertain significance ★ ⚠ same type
CPEB3 p.Ala254Pro Uncertain significance ★ ⚠ same type
CPEB3 p.Ala388Thr Uncertain significance ★ ⚠ same type
CPEB3 p.Ala409Gly Uncertain significance ★ ⚠ same type
CPEB3 p.Ala61Val 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/cpeb3-p-pro166arg (accessed [today's date]).

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