Is ASPM p.Pro27= (c.81C>A) pathogenic?

ASPM p.Pro27= (c.81C>A) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0297%, nfe); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Pro27= (c.81C>A)?

ASPM p.Pro27= (c.81C>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Pro27= (c.81C>A) in the general population?

ASPM p.Pro27= (c.81C>A) is ultra-rare (popmax 0.0297%, nfe) (gnomAD).

ASPM p.Pro27=

c.81C>A · rs369801034 · VCV157889

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, 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 -1.3	GERP -2.6
Overall
CADD	5.387	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0297% European (non-Finnish) · 350/1,179,474 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0261%

Overall 0.0241% 389/1,610,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0297%	3,370
South Asian	0.0198%	5,058
Middle Eastern	0.0175%	5,716
Remaining individualsnot grpmax-eligible	0.0128%	7,797
East Asian	0.0112%	8,958
Admixed American	0.005%	19,995
Finnishnot grpmax-eligible	0.00322%	31,031
African / African-American	0.00267%	37,470

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.Pro27=
Coding: c.81C>A
MANE Select: NM_018136
dbSNP: rs369801034
Type: single nucleotide variant
Location: chr1:197146357 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 27: 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 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-pro27 (accessed [today's date]).

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