Is CNNM4 p.Arg521Trp (c.1561C>T) pathogenic?

CNNM4 p.Arg521Trp (c.1561C>T) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.5465); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with CNNM4 p.Arg521Trp (c.1561C>T)?

CNNM4 p.Arg521Trp (c.1561C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM4 p.Arg521Trp (c.1561C>T) in the general population?

CNNM4 p.Arg521Trp (c.1561C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CNNM4 p.Arg521Trp (c.1561C>T)?

AlphaMissense predicts ambiguous (score 0.5465) — an in-silico prediction, not a clinical call.

CNNM4 p.Arg521Trp

c.1561C>T · rs772498225 · VCV1039574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5465	ambiguous
REVEL	0.507	indeterminate
SaProt	LLR -14.34	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.65, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · 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 0.00439% South Asian · 4/91,090 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,773
European (non-Finnish)	0.00246%	40,692
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg521Trp
Coding: c.1561C>T
MANE Select: NM_020184
dbSNP: rs772498225
Type: single nucleotide variant
Location: chr2:96797527 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.20 · 6 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM4 p.Arg521Gln Uncertain significance ★ ⚠ same residue
CNNM4 p.Ala297Gly Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala35Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala538Val Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala598Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg153Gln Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg178Lys 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-arg521trp (accessed [today's date]).

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