Is CNNM4 p.Leu29fs (c.86del) pathogenic?

CNNM4 p.Leu29fs (c.86del) is classified Pathogenic in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-03). Very rare (popmax 0.000271%, nfe).

How common is CNNM4 p.Leu29fs (c.86del) in the general population?

CNNM4 p.Leu29fs (c.86del) is very rare (popmax 0.000271%, nfe) (gnomAD).

CNNM4 p.Leu29fs

c.86del · rs2469450369 · VCV2013699

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000271%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.46	GERP -0.61, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000271% European (non-Finnish) · 3/1,106,852 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000227% 3/1,318,812 alleles · very rare

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.Leu29fs
Coding: c.86del
MANE Select: NM_020184
dbSNP: rs2469450369
Type: Deletion
Location: chr2:96761085 (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.Leu29= Likely benign ★ same residue
CNNM4 c.1402+22del Benign/Likely benign ★★ same type
CNNM4 p.Gly735_Thr737del Likely benign ★★ same type
CNNM4 p.Asn250fs Pathogenic ★ same type
CNNM4 p.Asp114fs Pathogenic ★ same type
CNNM4 p.Asp157fs Pathogenic ★ same type
CNNM4 p.Asp433fs Pathogenic ★ same type
CNNM4 p.Gly205_Leu206del Pathogenic ★ 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-leu29fs (accessed [today's date]).

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