Is MCM4 p.Thr53= (c.159C>T) pathogenic?

MCM4 p.Thr53= (c.159C>T) is classified Conflicting classifications of pathogenicity in MCM4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-01). Rare (popmax 0.129%, eas); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Thr53= (c.159C>T) in the general population?

MCM4 p.Thr53= (c.159C>T) is rare (popmax 0.129%, eas) (gnomAD).

MCM4 p.Thr53=

Q: What condition is associated with MCM4 p.Thr53= (c.159C>T)?

MCM4 p.Thr53= (c.159C>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.159C>T · rs775056163 · VCV363212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.129%, eas)

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.
REVEL	0.045	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -2
Overall
CADD	6.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.129% East Asian · 58/44,900 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.093%

Overall 0.00378% 61/1,614,082 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.129%	774
European (non-Finnish)	0.000254%	393,348

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.Thr53=
Coding: c.159C>T
MANE Select: NM_182746
dbSNP: rs775056163
Type: single nucleotide variant
Location: chr8:47961604 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 53: the 'disordered' region

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.Thr53Ala 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-thr53 (accessed [today's date]).

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