Is ASPM p.Ala1767Pro (c.5299G>C) pathogenic?

ASPM p.Ala1767Pro (c.5299G>C) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-20). AlphaMissense: ambiguous (0.4072); Rare (popmax 0.447%, afr); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ala1767Pro (c.5299G>C)?

ASPM p.Ala1767Pro (c.5299G>C) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ala1767Pro (c.5299G>C) in the general population?

ASPM p.Ala1767Pro (c.5299G>C) is rare (popmax 0.447%, afr) (gnomAD).

What do computational predictors say about ASPM p.Ala1767Pro (c.5299G>C)?

AlphaMissense predicts ambiguous (score 0.4072) — an in-silico prediction, not a clinical call.

ASPM p.Ala1767Pro

c.5299G>C · rs142536561 · VCV157833

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4072 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.447%, afr)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.4072	ambiguous
REVEL	0.322	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	0.25	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 0.447% African / African-American · 335/74,910 alleles

Filtering AF 0.408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.392%

Overall 0.0254% 409/1,612,516 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.447%	224
Remaining individualsnot grpmax-eligible	0.0352%	2,838
Admixed American	0.0167%	5,980
Middle Eastern	0.0165%	6,052
East Asian	0.00446%	22,411
South Asian	0.00329%	30,349
European (non-Finnish)	0.00305%	32,758

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.Ala1767Pro
Coding: c.5299G>C
MANE Select: NM_018136
dbSNP: rs142536561
Type: single nucleotide variant
Location: chr1:197103952 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1767: the iq 7 domain

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-ala1767pro (accessed [today's date]).

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