Is MCM4 p.Val67Met (c.199G>A) pathogenic?

MCM4 p.Val67Met (c.199G>A) is classified Uncertain significance in MCM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-07). AlphaMissense: likely benign (0.0814); Very rare (popmax 0.00017%, nfe); Associated with primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency.

How common is MCM4 p.Val67Met (c.199G>A) in the general population?

MCM4 p.Val67Met (c.199G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MCM4 p.Val67Met (c.199G>A)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

MCM4 p.Val67Met

Q: What condition is associated with MCM4 p.Val67Met (c.199G>A)?

MCM4 p.Val67Met (c.199G>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.199G>A · rs755044869 · VCV363214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0814 · 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	0.0814	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.54	GERP -3.2
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	0.168	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) · 2/1,178,998 alleles

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

Overall 0.000744% 12/1,612,526 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,955
European (non-Finnish)grpmax	0.00017%	589,498

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val67Met
Coding: c.199G>A
MANE Select: NM_182746
dbSNP: rs755044869
Type: single nucleotide variant
Location: chr8:47961644 (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 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-val67met (accessed [today's date]).

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