Is CNNM4 p.Val475Met (c.1423G>A) pathogenic?

CNNM4 p.Val475Met (c.1423G>A) is classified Likely pathogenic in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-20). AlphaMissense: likely pathogenic (0.996); Very rare (popmax 0.00223%, eas); Associated with Jalili syndrome.

What condition is associated with CNNM4 p.Val475Met (c.1423G>A)?

CNNM4 p.Val475Met (c.1423G>A) is associated with Jalili syndrome (ClinVar).

How common is CNNM4 p.Val475Met (c.1423G>A) in the general population?

CNNM4 p.Val475Met (c.1423G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNNM4 p.Val475Met (c.1423G>A)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CNNM4 p.Val475Met

c.1423G>A · VCV3340493

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Jalili syndrome

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic ✓ concordant with ClinVar · top 9% in CNNM4
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -12.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	34.0	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 0.00223% East Asian · 1/44,864 alleles

Overall 0.000137% 2/1,461,180 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
European (non-Finnish)	8.47e-05%	1,179,994

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.Val475Met
Coding: c.1423G>A
MANE Select: NM_020184
Type: single nucleotide variant
Location: chr2:96797032 (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 475: 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-val475met (accessed [today's date]).

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