Is CELF4 p.Leu73Ile (c.217C>A) pathogenic?

CELF4 p.Leu73Ile (c.217C>A) is classified Likely benign in CELF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.2828); Ultra-rare (popmax 0.0168%, nfe).

How common is CELF4 p.Leu73Ile (c.217C>A) in the general population?

CELF4 p.Leu73Ile (c.217C>A) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about CELF4 p.Leu73Ile (c.217C>A)?

AlphaMissense predicts likely benign (score 0.2828) — an in-silico prediction, not a clinical call.

CELF4 p.Leu73Ile

c.217C>A · VCV4225194

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2828	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -3.96	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 8.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 244 kb · p 6e-06 · regional, not allelic
Overall
CADD	29.5	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 0.0168% European (non-Finnish) · 198/1,179,446 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0128% 207/1,613,154 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,957
Remaining individualsnot grpmax-eligible	0.0064%	15,616
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,550
African / African-American	0.00267%	37,512
Admixed American	0.00167%	59,934
Finnishnot grpmax-eligible	0.00156%	64,024

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.Leu73Ile
Coding: c.217C>A
MANE Select: NM_020180
Type: single nucleotide variant
Location: chr18:37565425 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.84 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.70 · 2 PDB
Residue 73: the rrm 1 domain; an α-helix; 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.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
CELF4 c.370-67640C>A Uncertain significance ★ same type
CELF4 c.577+2T>G 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-leu73ile (accessed [today's date]).

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