Is CELF2 p.Ala46Val (c.137C>T) pathogenic?

CELF2 p.Ala46Val (c.137C>T) is classified Uncertain significance in CELF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely pathogenic (0.7513); Very rare (popmax 8.47e-05%, nfe).

How common is CELF2 p.Ala46Val (c.137C>T) in the general population?

CELF2 p.Ala46Val (c.137C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CELF2 p.Ala46Val (c.137C>T)?

AlphaMissense predicts likely pathogenic (score 0.7513) — an in-silico prediction, not a clinical call.

CELF2 p.Ala46Val

c.137C>T · VCV4225189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7513 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7513	likely pathogenic
REVEL	0.361	indeterminate
SaProt	LLR -11.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 156 kb · p 7.3e-29 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A39V vs ClinVar A46V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,188 alleles · very rare exomes 1/1,461,886 · genomes 0/152,302 · joint denominator

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.Ala46Val
Coding: c.137C>T
MANE Select: NM_001326342
Type: single nucleotide variant
Location: chr10:11165548 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.26 · 7 PDB
Residue 39 UniProt numbering: 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-ala46val (accessed [today's date]).

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