Is CNNM4 p.Leu135Phe (c.403C>T) pathogenic?

CNNM4 p.Leu135Phe (c.403C>T) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-15). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CNNM4 p.Leu135Phe (c.403C>T)?

CNNM4 p.Leu135Phe (c.403C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM4 p.Leu135Phe (c.403C>T) in the general population?

CNNM4 p.Leu135Phe (c.403C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CNNM4 p.Leu135Phe (c.403C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

CNNM4 p.Leu135Phe

c.403C>T · rs745779788 · VCV1465846

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.63	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 -0.19	GERP -2.8, phastCons 0.25
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	10.01	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 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.000169%	590,023

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.Leu135Phe
Coding: c.403C>T
MANE Select: NM_020184
dbSNP: rs745779788
Type: single nucleotide variant
Location: chr2:96761402 (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.Leu135= Likely benign ★ 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-leu135phe (accessed [today's date]).

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