Is CELF2 p.Arg227His (c.680G>A) pathogenic?

CELF2 p.Arg227His (c.680G>A) is classified Uncertain significance in CELF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.7859); Very rare (popmax 0.00181%, amr).

How common is CELF2 p.Arg227His (c.680G>A) in the general population?

CELF2 p.Arg227His (c.680G>A) is very rare (popmax 0.00181%, amr) (gnomAD).

What do computational predictors say about CELF2 p.Arg227His (c.680G>A)?

AlphaMissense predicts likely pathogenic (score 0.7859) — an in-silico prediction, not a clinical call.

CELF2 p.Arg227His

c.680G>A · VCV4651855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00181%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7859	likely pathogenic
REVEL	0.385	indeterminate
SaProt	LLR -12.02	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 156 kb · p 7.3e-29 · regional, not allelic
Overall
CADD	33.0	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 R220H vs ClinVar R227H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00181% Admixed American · 1/55,394 alleles

Filtering AF 0.000299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000639% 10/1,563,810 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00181%	55,394
Finnishnot grpmax-eligible	0.00159%	62,830
European (non-Finnish)	0.000695%	143,906

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.Arg227His
Coding: c.680G>A
MANE Select: NM_001326342
Type: single nucleotide variant
Location: chr10:11270727 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.26 · 7 PDB
Residue 227: 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-arg227his (accessed [today's date]).

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