Is ASPM p.Arg489= (c.1467A>G) pathogenic?

ASPM p.Arg489= (c.1467A>G) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-04). Ultra-rare (popmax 0.0313%, nfe); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg489= (c.1467A>G)?

ASPM p.Arg489= (c.1467A>G) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg489= (c.1467A>G) in the general population?

ASPM p.Arg489= (c.1467A>G) is ultra-rare (popmax 0.0313%, nfe) (gnomAD).

ASPM p.Arg489=

c.1467A>G · rs146561469 · VCV294653

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, nfe)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.61, phastCons 1
Overall
CADD	8.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0313% European (non-Finnish) · 369/1,179,574 alleles

Filtering AF 0.0286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0272% 439/1,613,540 alleles · ultra-rare exomes 394/1,461,378 · genomes 45/152,162 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.172%	580
European (non-Finnish)grpmax	0.0313%	3,197
Remaining individualsnot grpmax-eligible	0.0128%	7,809
African / African-American	0.00668%	14,981
Finnishnot grpmax-eligible	0.00625%	16,009
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,076

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: ASPM
Protein: p.Arg489=
Coding: c.1467A>G
MANE Select: NM_018136
dbSNP: rs146561469
Type: single nucleotide variant
Location: chr1:197142785 (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 c.2419+2T>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.2488-1G>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.2936+5G>A Likely pathogenic ★★ same condition
ASPM c.3082+1G>C Pathogenic/Likely pathogenic ★★ same condition
ASPM c.9084+5G>A Likely pathogenic ★★ same condition
ASPM p.Arg1019Ter Pathogenic ★★ same condition
ASPM p.Arg1271Ter Pathogenic ★★ same condition
ASPM p.Arg1538Ter 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-arg489 (accessed [today's date]).

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