Is CPEB3 p.Ser253Arg (c.759C>A) pathogenic?

CPEB3 p.Ser253Arg (c.759C>A) is classified Uncertain significance in CPEB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). AlphaMissense: likely pathogenic (0.9186); Very rare (popmax 0.000696%, nfe).

How common is CPEB3 p.Ser253Arg (c.759C>A) in the general population?

CPEB3 p.Ser253Arg (c.759C>A) is very rare (popmax 0.000696%, nfe) (gnomAD).

What do computational predictors say about CPEB3 p.Ser253Arg (c.759C>A)?

AlphaMissense predicts likely pathogenic (score 0.9186) — an in-silico prediction, not a clinical call.

CPEB3 p.Ser253Arg

c.759C>A · rs376818546 · VCV2239663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000696%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9186	likely pathogenic
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -2.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 129 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.7	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 0.000696% European (non-Finnish) · 8/1,148,670 alleles

Filtering AF 0.0003% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000515% 8/1,554,124 alleles · very rare

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.Ser253Arg
Coding: c.759C>A
MANE Select: NM_014912
dbSNP: rs376818546
Type: single nucleotide variant
Location: chr10:92239592 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 58.59 · 6 PDB

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

Similar variants

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
CPEB3 p.Ala64Thr 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-ser253arg (accessed [today's date]).

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