Is ASPM p.Gln421fs (c.1260_1266del) pathogenic?

ASPM p.Gln421fs (c.12601266del) is classified Pathogenic in ASPM (ClinVar, No assertion criteria, 2 submitters; last evaluated 2002-10-01). Very rare (popmax 0.00329%, sas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Gln421fs (c.1260_1266del)?

ASPM p.Gln421fs (c.1260_1266del) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Gln421fs (c.1260_1266del) in the general population?

ASPM p.Gln421fs (c.1260_1266del) is very rare (popmax 0.00329%, sas) (gnomAD).

ASPM p.Gln421fs

c.1260_1266del · rs199422139 · VCV21552

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.31	GERP -1.4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,068 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,610 alleles · very rare

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: ASPM
Protein: p.Gln421fs
Coding: c.1260_1266del
MANE Select: NM_018136
dbSNP: rs199422139
Type: Deletion
Location: chr1:197142986 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 421: the 'disordered' region

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

Disease context

microcephaly 5, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPM p.Arg2005fs Pathogenic ★★ same condition
ASPM p.Asn1095fs Likely pathogenic ★★ same condition
ASPM p.Asn324fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Asn394fs Pathogenic ★★ same condition
ASPM p.Asp1285fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Asp990fs Pathogenic ★★ same condition
ASPM p.Gln2904fs Pathogenic ★★ same condition
ASPM p.Glu2731fs Pathogenic ★★ 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/aspm-p-gln421fs (accessed [today's date]).

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