Is MCM4 p.Lys688= (c.2064G>A) pathogenic?

MCM4 p.Lys688= (c.2064G>A) is classified Benign/Likely benign in MCM4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-22). Low-frequency (popmax 1.37%, mid); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Lys688= (c.2064G>A) in the general population?

MCM4 p.Lys688= (c.2064G>A) is low-frequency (popmax 1.37%, mid) (gnomAD).

MCM4 p.Lys688=

Q: What condition is associated with MCM4 p.Lys688= (c.2064G>A)?

MCM4 p.Lys688= (c.2064G>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.2064G>A · rs143488457 · VCV522231

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.37%, 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 2.2	GERP -0.64, phastCons 1
Overall
CADD	7.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.37% Middle Eastern · 83/6,060 alleles

Filtering AF 1.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.173% 2,799/1,614,160 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.37%	73
African / African-American	1.13%	88
Admixed American	0.487%	206
Remaining individualsnot grpmax-eligible	0.347%	288
Ashkenazi Jewishnot grpmax-eligible	0.118%	846
European (non-Finnish)	0.111%	897
South Asian	0.00329%	30,362
Finnishnot grpmax-eligible	0.00312%	32,008
East Asian	0.00223%	44,880

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.Lys688=
Coding: c.2064G>A
MANE Select: NM_182746
dbSNP: rs143488457
Type: single nucleotide variant
Location: chr8:47972992 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 688: an α-helix; the mcm c-terminal aaa(+) atpase domain

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.Lys688Arg Conflicting classifications of pathogenicity ★ ⚠ 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-lys688 (accessed [today's date]).

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