Is CNNM4 p.Pro656= (c.1968C>G) pathogenic?

CNNM4 p.Pro656= (c.1968C>G) is classified Likely benign in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Very rare (popmax 0.000339%, nfe).

How common is CNNM4 p.Pro656= (c.1968C>G) in the general population?

CNNM4 p.Pro656= (c.1968C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

CNNM4 p.Pro656=

c.1968C>G · rs748121320 · VCV1665151

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

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 -3.8	GERP -2.6
Overall
CADD	0.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,010 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,942 alleles · very rare exomes 2/1,461,886 · genomes 2/152,056 · joint denominator

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.Pro656=
Coding: c.1968C>G
MANE Select: NM_020184
dbSNP: rs748121320
Type: single nucleotide variant
Location: chr2:96808580 (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

Similar variants

CNNM4 p.Pro656Ala Uncertain significance ★ ⚠ same residue
CNNM4 p.Arg519Ter Pathogenic ★★ same type
CNNM4 p.Arg605Ter Pathogenic ★★ same type
CNNM4 p.Gln564Ter Pathogenic ★★ same type
CNNM4 p.Gln717Ter Pathogenic/Likely pathogenic ★★ same type
CNNM4 c.2130+5G>A Uncertain significance ★★ same type
CNNM4 c.*1126G>A Uncertain significance ★★ same type
CNNM4 p.Ala297Gly 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/cnnm4-p-pro656 (accessed [today's date]).

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