Is ASPM p.Ala2817Ser (c.8449G>T) pathogenic?

ASPM p.Ala2817Ser (c.8449G>T) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1227); Low-frequency (popmax 1.68%, eas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ala2817Ser (c.8449G>T)?

ASPM p.Ala2817Ser (c.8449G>T) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ala2817Ser (c.8449G>T) in the general population?

ASPM p.Ala2817Ser (c.8449G>T) is low-frequency (popmax 1.68%, eas) (gnomAD).

What do computational predictors say about ASPM p.Ala2817Ser (c.8449G>T)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

ASPM p.Ala2817Ser

c.8449G>T · rs117963393 · VCV157892

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.68%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.177	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.069	GERP -0.17, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	13.65	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 1.68% East Asian · 752/44,804 alleles

Filtering AF 1.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.54%

Overall 0.053% 854/1,612,538 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.68%	60
Remaining individualsnot grpmax-eligible	0.0673%	1,487
South Asian	0.0439%	2,277
Middle Eastern	0.0165%	6,050
Admixed American	0.00669%	14,949
European (non-Finnish)	0.00127%	78,608

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.Ala2817Ser
Coding: c.8449G>T
MANE Select: NM_018136
dbSNP: rs117963393
Type: single nucleotide variant
Location: chr1:197100802 (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.Ala2817Asp Uncertain significance ★★ 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-ala2817ser (accessed [today's date]).

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