Is CNNM4 p.Phe326Leu (c.978T>G) pathogenic?

CNNM4 p.Phe326Leu (c.978T>G) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.3965); Very rare (popmax 0.00432%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CNNM4 p.Phe326Leu (c.978T>G)?

CNNM4 p.Phe326Leu (c.978T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM4 p.Phe326Leu (c.978T>G) in the general population?

CNNM4 p.Phe326Leu (c.978T>G) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about CNNM4 p.Phe326Leu (c.978T>G)?

AlphaMissense predicts ambiguous (score 0.3965) — an in-silico prediction, not a clinical call.

CNNM4 p.Phe326Leu

c.978T>G · VCV4616017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3965	ambiguous
REVEL	0.249	benign-leaning
SaProt	LLR -6.31	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.99	GERP -3.3
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	13.38	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 0.00432% European (non-Finnish) · 51/1,180,014 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00341% 55/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,138
Remaining individualsnot grpmax-eligible	0.0032%	31,256
African / African-American	0.00267%	37,498

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.Phe326Leu
Coding: c.978T>G
MANE Select: NM_020184
Type: single nucleotide variant
Location: chr2:96761977 (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 326: the cnnm transmembrane domain

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.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
CNNM4 p.Arg338Gly 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-phe326leu (accessed [today's date]).

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