Is ASPM p.Ala194Asp (c.581C>A) pathogenic?

ASPM p.Ala194Asp (c.581C>A) is classified Benign/Likely benign in ASPM (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-17). AlphaMissense: ambiguous (0.4323); Rare (popmax 0.934%, eas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ala194Asp (c.581C>A)?

ASPM p.Ala194Asp (c.581C>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ala194Asp (c.581C>A) in the general population?

ASPM p.Ala194Asp (c.581C>A) is rare (popmax 0.934%, eas) (gnomAD).

What do computational predictors say about ASPM p.Ala194Asp (c.581C>A)?

AlphaMissense predicts ambiguous (score 0.4323) — an in-silico prediction, not a clinical call.

ASPM p.Ala194Asp

c.581C>A · rs141532484 · VCV282730

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4323 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.934%, eas)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.4323	ambiguous
REVEL	0.086	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,369 bp · p 0.063 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.934% East Asian · 419/44,870 alleles

Filtering AF 0.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.831%

Overall 0.0304% 491/1,613,772 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.934%	107
Remaining individualsnot grpmax-eligible	0.0832%	1,202
Admixed American	0.0267%	3,751
South Asian	0.0022%	45,542
European (non-Finnish)	0.00017%	589,957

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.Ala194Asp
Coding: c.581C>A
MANE Select: NM_018136
dbSNP: rs141532484
Type: single nucleotide variant
Location: chr1:197143671 (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.Ala194= Conflicting classifications of pathogenicity ★ same residue
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

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-ala194asp (accessed [today's date]).

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