Is CNNM4 p.Asn85Asp (c.253A>G) pathogenic?

CNNM4 p.Asn85Asp (c.253A>G) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-22). AlphaMissense: likely benign (0.0723); Ultra-rare (popmax 0.0966%, amr); Associated with Jalili syndrome.

What condition is associated with CNNM4 p.Asn85Asp (c.253A>G)?

CNNM4 p.Asn85Asp (c.253A>G) is associated with Jalili syndrome (ClinVar).

How common is CNNM4 p.Asn85Asp (c.253A>G) in the general population?

CNNM4 p.Asn85Asp (c.253A>G) is ultra-rare (popmax 0.0966%, amr) (gnomAD).

What do computational predictors say about CNNM4 p.Asn85Asp (c.253A>G)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

CNNM4 p.Asn85Asp

c.253A>G · rs138690324 · VCV337580

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Jalili syndrome

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.87	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 0.37	GERP -2.8, phastCons 0.036
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	9.355	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 0.0966% Admixed American · 58/60,030 alleles

Filtering AF 0.0767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0695%

Overall 0.00477% 77/1,614,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0966%	1,035
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.004%	25,017
European (non-Finnish)	0.000339%	294,999

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.Asn85Asp
Coding: c.253A>G
MANE Select: NM_020184
dbSNP: rs138690324
Type: single nucleotide variant
Location: chr2:96761252 (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

Jalili syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
CNNM4 p.Arg523Gln Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg651Cys 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-asn85asp (accessed [today's date]).

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