Is MCM4 p.Phe576= (c.1728C>T) pathogenic?

MCM4 p.Phe576= (c.1728C>T) is classified Conflicting classifications of pathogenicity in MCM4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-01). Rare (popmax 0.115%, mid); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Phe576= (c.1728C>T) in the general population?

MCM4 p.Phe576= (c.1728C>T) is rare (popmax 0.115%, mid) (gnomAD).

MCM4 p.Phe576=

Q: What condition is associated with MCM4 p.Phe576= (c.1728C>T)?

MCM4 p.Phe576= (c.1728C>T) 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.1728C>T · rs148525401 · VCV909877

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

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 -1.2	GERP -4.8, phastCons 0.001
Overall
CADD	8.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.0133% 214/1,613,714 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
African / African-American	0.0373%	2,679
Admixed American	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0224%	4,464
European (non-Finnish)	0.0118%	8,487
South Asian	0.0033%	30,348
Finnishnot grpmax-eligible	0.00313%	31,998

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.Phe576=
Coding: c.1728C>T
MANE Select: NM_182746
dbSNP: rs148525401
Type: single nucleotide variant
Location: chr8:47970804 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 576: the mcm c-terminal aaa(+) atpase domain; a β-strand

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 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
MCM4 p.Arg554Lys 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-phe576 (accessed [today's date]).

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