Is CNNM4 p.Val752Met (c.2254G>A) pathogenic?

CNNM4 p.Val752Met (c.2254G>A) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.0125%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CNNM4 p.Val752Met (c.2254G>A)?

CNNM4 p.Val752Met (c.2254G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM4 p.Val752Met (c.2254G>A) in the general population?

CNNM4 p.Val752Met (c.2254G>A) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about CNNM4 p.Val752Met (c.2254G>A)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

CNNM4 p.Val752Met

c.2254G>A · rs373978823 · VCV846349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -7.89	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 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	21.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% European (non-Finnish) · 147/1,180,044 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00942% 152/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,027
African / African-American	0.00534%	18,734
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Val752Met
Coding: c.2254G>A
MANE Select: NM_020184
dbSNP: rs373978823
Type: single nucleotide variant
Location: chr2:96809443 (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.Val752Gly Conflicting classifications of pathogenicity ★ ⚠ 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-val752met (accessed [today's date]).

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