Is CPEB4 p.Pro375Leu (c.1124C>T) pathogenic?

CPEB4 p.Pro375Leu (c.1124C>T) is classified Uncertain significance in CPEB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-19). AlphaMissense: likely benign (0.1375); Very rare (popmax 0.00536%, afr).

How common is CPEB4 p.Pro375Leu (c.1124C>T) in the general population?

CPEB4 p.Pro375Leu (c.1124C>T) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about CPEB4 p.Pro375Leu (c.1124C>T)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

CPEB4 p.Pro375Leu

c.1124C>T · rs373430313 · VCV2619487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.55	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 5.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 55 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.9	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 0.00536% African / African-American · 4/74,656 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00131% 21/1,603,672 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,664
European (non-Finnish)	0.00145%	69,101

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: CPEB4
Protein: p.Pro375Leu
Coding: c.1124C>T
MANE Select: NM_030627
dbSNP: rs373430313
Type: single nucleotide variant
Location: chr5:173890857 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.58 · 3 PDB

Full CPEB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPEB4 p.Ala104Ser Uncertain significance ★ ⚠ same type
CPEB4 p.Ala197Pro Uncertain significance ★ ⚠ same type
CPEB4 p.Ala349Ser Uncertain significance ★ ⚠ same type
CPEB4 p.Ala610Thr Uncertain significance ★ ⚠ same type
CPEB4 p.Ala80Thr Uncertain significance ★ ⚠ same type
CPEB4 p.Arg134Lys Uncertain significance ★ ⚠ same type
CPEB4 p.Arg319Lys Uncertain significance ★ ⚠ same type
CPEB4 p.Arg350Cys 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/cpeb4-p-pro375leu (accessed [today's date]).

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