Is MCM4 p.Pro81Ser (c.241C>T) pathogenic?

MCM4 p.Pro81Ser (c.241C>T) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00017%, nfe); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Pro81Ser (c.241C>T) in the general population?

MCM4 p.Pro81Ser (c.241C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MCM4 p.Pro81Ser (c.241C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

MCM4 p.Pro81Ser

Q: What condition is associated with MCM4 p.Pro81Ser (c.241C>T)?

MCM4 p.Pro81Ser (c.241C>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.241C>T · rs886062975 · VCV363216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.26	gain · loss 0.19 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 0.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	22.0	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 0.00017% European (non-Finnish) · 2/1,179,926 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,718 alleles · very rare exomes 1/1,461,636 · genomes 1/152,082 · joint denominator

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.Pro81Ser
Coding: c.241C>T
MANE Select: NM_182746
dbSNP: rs886062975
Type: single nucleotide variant
Location: chr8:47962058 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB

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.Pro81Leu 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-pro81ser (accessed [today's date]).

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