Is ASPM p.Arg1576fs (c.4728_4729del) pathogenic?

ASPM p.Arg1576fs (c.47284729del) is classified Pathogenic/Likely pathogenic in ASPM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-06-18). Very rare (popmax 0.00446%, eas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg1576fs (c.4728_4729del)?

ASPM p.Arg1576fs (c.4728_4729del) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg1576fs (c.4728_4729del) in the general population?

ASPM p.Arg1576fs (c.4728_4729del) is very rare (popmax 0.00446%, eas) (gnomAD).

ASPM p.Arg1576fs

c.4728_4729del · rs587783245 · VCV157824

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 18 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.5	GERP -0.97
Overall
CADD	22.9	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

Grpmax group 0.00446% East Asian · 2/44,806 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000558% 9/1,612,552 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,403
Admixed American	0.00335%	29,864
African / African-American	0.00267%	37,402
Finnishnot grpmax-eligible	0.00157%	63,804
European (non-Finnish)	0.00017%	589,696

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.Arg1576fs
Coding: c.4728_4729del
MANE Select: NM_018136
dbSNP: rs587783245
Type: Microsatellite
Location: chr1:197104522 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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.Arg1576Gly Uncertain significance ★ same residue
ASPM p.Arg1315fs Pathogenic ★★ same condition
ASPM p.Arg1416_Tyr1417insTer Pathogenic ★★ same condition
ASPM p.Arg2229fs Pathogenic ★★ same condition
ASPM p.Asn653fs Pathogenic ★★ same condition
ASPM p.Gln2836fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Glu385fs Pathogenic ★★ same condition
ASPM p.Ile2113fs 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-arg1576fs (accessed [today's date]).

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