Is CNNM4 p.Ile474= (c.1422C>T) pathogenic?

CNNM4 p.Ile474= (c.1422C>T) is classified Conflicting classifications of pathogenicity in CNNM4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-19). Ultra-rare (popmax 0.0183%, amr); Associated with Jalili syndrome.

What condition is associated with CNNM4 p.Ile474= (c.1422C>T)?

CNNM4 p.Ile474= (c.1422C>T) is associated with Jalili syndrome (ClinVar).

How common is CNNM4 p.Ile474= (c.1422C>T) in the general population?

CNNM4 p.Ile474= (c.1422C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

CNNM4 p.Ile474=

c.1422C>T · rs766518199 · VCV896487

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

Jalili syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.8
Overall
CADD	12.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,990 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00174% 28/1,613,290 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,454
European (non-Finnish)	0.00136%	73,750
South Asian	0.0011%	91,044

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: CNNM4
Protein: p.Ile474=
Coding: c.1422C>T
MANE Select: NM_020184
dbSNP: rs766518199
Type: single nucleotide variant
Location: chr2:96797031 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.20 · 6 PDB
Residue 474: the cbs 2 domain

Full CNNM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Jalili syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM4 p.Arg519Ter Pathogenic ★★ same condition
CNNM4 p.Gln564Ter Pathogenic ★★ same condition
CNNM4 p.Gln717Ter Pathogenic/Likely pathogenic ★★ same condition
CNNM4 c.2130+5G>A Uncertain significance ★★ same condition
CNNM4 c.*1126G>A Uncertain significance ★★ same condition
CNNM4 p.Ala598Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg523Gln Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg651Cys Uncertain significance ★★ ⚠ same condition

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/cnnm4-p-ile474 (accessed [today's date]).

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