Is CELF4 p.Pro219Leu (c.656C>T) pathogenic?

CELF4 p.Pro219Leu (c.656C>T) is classified Uncertain significance in CELF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-10). AlphaMissense: ambiguous (0.3847); Very rare (popmax 8.53e-05%, nfe).

How common is CELF4 p.Pro219Leu (c.656C>T) in the general population?

CELF4 p.Pro219Leu (c.656C>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about CELF4 p.Pro219Leu (c.656C>T)?

AlphaMissense predicts ambiguous (score 0.3847) — an in-silico prediction, not a clinical call.

CELF4 p.Pro219Leu

c.656C>T · VCV4868712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3847	ambiguous
REVEL	0.603	indeterminate
SaProt	LLR -12.10	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 765 bp · p 0.00017 · regional, not allelic
Overall
CADD	32.0	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 8.53e-05% European (non-Finnish) · 1/1,172,966 alleles

Overall 6.93e-05% 1/1,443,452 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: CELF4
Protein: p.Pro219Leu
Coding: c.656C>T
MANE Select: NM_020180
Type: single nucleotide variant
Location: chr18:37274806 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.84 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.70 · 2 PDB
Residue 219: the rrm 2 domain; the 'sufficient for rna-binding and mse-dependent splicing activity' region

Full CELF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELF4 p.Pro219Thr Uncertain significance ★ same residue
CELF4 p.Pro219Arg Likely benign ★ same residue
CELF4 p.Gly193Val Uncertain significance ★★ ⚠ same type
CELF4 p.Ala381= Benign/Likely benign ★★ same type
CELF4 p.Pro127= Benign ★★ same type
CELF4 p.Pro406= Benign ★★ same type
CELF4 p.Glu76Ter Pathogenic ★ same type
CELF4 c.1165+2T>C 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/celf4-p-pro219leu (accessed [today's date]).

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