Is CNNM4 p.Pro315Leu (c.944C>T) pathogenic?

CNNM4 p.Pro315Leu (c.944C>T) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.569); Very rare (popmax 0.000678%, nfe); Associated with Jalili syndrome.

What condition is associated with CNNM4 p.Pro315Leu (c.944C>T)?

CNNM4 p.Pro315Leu (c.944C>T) is associated with Jalili syndrome (ClinVar).

How common is CNNM4 p.Pro315Leu (c.944C>T) in the general population?

CNNM4 p.Pro315Leu (c.944C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CNNM4 p.Pro315Leu (c.944C>T)?

AlphaMissense predicts likely pathogenic (score 0.569) — an in-silico prediction, not a clinical call.

CNNM4 p.Pro315Leu

c.944C>T · rs2469454871 · VCV3065365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Jalili syndrome

Computational evidence

Protein change
AlphaMissense	0.569	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -12.60	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000678% European (non-Finnish) · 8/1,180,030 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,884 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.Pro315Leu
Coding: c.944C>T
MANE Select: NM_020184
dbSNP: rs2469454871
Type: single nucleotide variant
Location: chr2:96761943 (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 315: the cnnm transmembrane 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.Pro315Ser Uncertain significance ★ ⚠ same residue
CNNM4 p.Pro315= Likely benign ★ same residue
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

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-pro315leu (accessed [today's date]).

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