Is CELF1 p.Val74Ile (c.220G>A) pathogenic?

CELF1 p.Val74Ile (c.220G>A) is classified Uncertain significance in CELF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-18). AlphaMissense: likely benign (0.0732); Very rare (popmax 0.00649%, nfe).

How common is CELF1 p.Val74Ile (c.220G>A) in the general population?

CELF1 p.Val74Ile (c.220G>A) is very rare (popmax 0.00649%, nfe) (gnomAD).

What do computational predictors say about CELF1 p.Val74Ile (c.220G>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

CELF1 p.Val74Ile

c.220G>A · VCV4225180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00649%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -8.92	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 27 kb · p 1.2e-24 · regional, not allelic
Overall
CADD	23.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V47I vs ClinVar V74I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00649% European (non-Finnish) · 76/1,171,796 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00485%

Overall 0.00483% 77/1,593,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00649%	15,418
Remaining individualsnot grpmax-eligible	0.00162%	61,552

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: CELF1
Protein: p.Val74Ile
Coding: c.220G>A
MANE Select: NM_001376376
Type: single nucleotide variant
Location: chr11:47488876 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.17 · 8 PDB
Residue 74: the rrm 1 domain; an α-helix

Full CELF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELF1 p.Ser507= Benign ★★ same type
CELF1 c.606+2T>A Uncertain significance ★ same type
CELF1 p.Ala237Thr Uncertain significance ★ ⚠ same type
CELF1 p.Ala401Val Uncertain significance ★ same type
CELF1 p.Ala99Val Uncertain significance ★ ⚠ same type
CELF1 p.Arg152Gln Uncertain significance ★ same type
CELF1 p.Arg506His Uncertain significance ★ ⚠ same type
CELF1 p.Arg60Gln 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/celf1-p-val74ile (accessed [today's date]).

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