Is ASPM p.Ser557fs (c.1671_1672del) pathogenic?

ASPM p.Ser557fs (c.16711672del) is classified Pathogenic in ASPM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-17). Very rare (popmax 0.005%, amr); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ser557fs (c.1671_1672del)?

ASPM p.Ser557fs (c.1671_1672del) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ser557fs (c.1671_1672del) in the general population?

ASPM p.Ser557fs (c.1671_1672del) is very rare (popmax 0.005%, amr) (gnomAD).

ASPM p.Ser557fs

c.1671_1672del · rs587783220 · VCV157783

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 -0.65	GERP -2.6

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00164% 24/1,461,564 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,010
European (non-Finnish)	0.0017%	58,989
Remaining individualsnot grpmax-eligible	0.0016%	62,492

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.Ser557fs
Coding: c.1671_1672del
MANE Select: NM_018136
dbSNP: rs587783220
Type: Deletion
Location: chr1:197142580 (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.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-ser557fs (accessed [today's date]).

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