Is MCM4 p.Val523= (c.1569G>A) pathogenic?

MCM4 p.Val523= (c.1569G>A) is classified Benign/Likely benign in MCM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Rare (popmax 0.537%, amr); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Val523= (c.1569G>A) in the general population?

MCM4 p.Val523= (c.1569G>A) is rare (popmax 0.537%, amr) (gnomAD).

MCM4 p.Val523=

Q: What condition is associated with MCM4 p.Val523= (c.1569G>A)?

MCM4 p.Val523= (c.1569G>A) is associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (ClinVar).

Q: How is Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1569G>A · rs765660789 · VCV363233

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.537%, amr)

Conditions

primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP 0.39, phastCons 0.8
Overall
CADD	8.382	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.537% Admixed American · 322/59,998 alleles

Filtering AF 0.488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.469%

Overall 0.0202% 326/1,614,050 alleles · rare exomes 301/1,461,894 · genomes 25/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.537%	186
Remaining individualsnot grpmax-eligible	0.0064%	15,621

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: MCM4
Protein: p.Val523=
Coding: c.1569G>A
MANE Select: NM_182746
dbSNP: rs765660789
Type: single nucleotide variant
Location: chr8:47970645 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 523: the mcm c-terminal aaa(+) atpase domain; an α-helix

Full MCM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MCM4 p.Val523Met Uncertain significance ★ same residue
MCM4 c.71-2A>G Pathogenic ★★ same condition
MCM4 c.-74C>T Uncertain significance ★★ same condition
MCM4 c.*56G>A Uncertain significance ★★ same condition
MCM4 p.Ala141Gly Uncertain significance ★★ ⚠ same condition
MCM4 p.Arg314Trp Uncertain significance ★★ ⚠ same condition
MCM4 p.Arg343His Uncertain significance ★★ same condition
MCM4 p.Arg422Trp 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/mcm4-p-val523 (accessed [today's date]).

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