Is AP1S1 p.Gln74Ter (c.220C>T) pathogenic?

AP1S1 p.Gln74Ter (c.220C>T) is classified Pathogenic/Likely pathogenic in AP1S1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-23). Absent from gnomAD v4.1; Associated with MEDNIK syndrome.

What condition is associated with AP1S1 p.Gln74Ter (c.220C>T)?

AP1S1 p.Gln74Ter (c.220C>T) is associated with MEDNIK syndrome (ClinVar).

How common is AP1S1 p.Gln74Ter (c.220C>T) in the general population?

AP1S1 p.Gln74Ter (c.220C>T) is absent from gnomAD v4.1 (gnomAD).

How is MEDNIK syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AP1S1 p.Gln74Ter

c.220C>T · rs1584203922 · VCV804403

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,582,544)

Conditions

MEDNIK syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,582,544). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: AP1S1
Protein: p.Gln74Ter
Coding: c.220C>T
MANE Select: NM_001283
dbSNP: rs1584203922
Type: single nucleotide variant
Location: chr7:101157414 (GRCh38)
Gene constraint: LOEUF 1.078 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.83 · 1 PDB

Full AP1S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MEDNIK syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MEDNIK syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

AP1S1 c.183-1G>C Pathogenic/Likely pathogenic ★★ same condition
AP1S1 c.183-2A>G Pathogenic ★★ same condition
AP1S1 c.291+2T>A Pathogenic/Likely pathogenic ★★ same condition
AP1S1 p.Tyr62Ter Pathogenic/Likely pathogenic ★★ same condition
AP1S1 c.182+78T>C Benign ★★ same condition
AP1S1 p.Glu100Lys Uncertain significance ★ ⚠ same condition
AP1S1 p.Asp122fs Likely pathogenic ★★ same condition
AP1S1 c.182+252C>T Benign ★★ same type

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/ap1s1-p-gln74ter (accessed [today's date]).

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