Is CELF2 p.Pro174Leu (c.521C>T) pathogenic?

CELF2 p.Pro174Leu (c.521C>T) is classified Uncertain significance in CELF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). AlphaMissense: ambiguous (0.3777); Very rare (popmax 8.47e-05%, nfe).

How common is CELF2 p.Pro174Leu (c.521C>T) in the general population?

CELF2 p.Pro174Leu (c.521C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CELF2 p.Pro174Leu (c.521C>T)?

AlphaMissense predicts ambiguous (score 0.3777) — an in-silico prediction, not a clinical call.

CELF2 p.Pro174Leu

c.521C>T · VCV3768817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3777	ambiguous
REVEL	0.447	indeterminate
SaProt	LLR -9.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 156 kb · p 7.3e-29 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P167L vs ClinVar P174L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 0.000657% 1/152,184 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: CELF2
Protein: p.Pro174Leu
Coding: c.521C>T
MANE Select: NM_001326342
Type: single nucleotide variant
Location: chr10:11257855 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.26 · 7 PDB
Residue 174: the rrm 2 domain; a β-strand; the 'necessary for rna-binding, tnnt2 exon 5 and nmda r1 exon 21 inclusion' region

Full CELF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELF2 p.Arg506Cys Pathogenic/Likely pathogenic ★★ same type
CELF2 p.Arg513His Likely pathogenic ★★ same type
CELF2 p.Gln237Ter Pathogenic/Likely pathogenic ★★ same type
CELF2 p.Ala135Thr Uncertain significance ★★ ⚠ same type
CELF2 p.Val95Leu Uncertain significance ★★ ⚠ same type
CELF2 p.Arg506His Pathogenic ★ same type
CELF2 p.Arg506Leu Pathogenic ★ same type
CELF2 p.Arg513Cys Likely pathogenic ★ 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/celf2-p-pro174leu (accessed [today's date]).

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