Is ASPM p.Pro226Ser (c.676C>T) pathogenic?

ASPM p.Pro226Ser (c.676C>T) is classified Uncertain significance in ASPM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-28). AlphaMissense: likely benign (0.0941); Ultra-rare (popmax 0.0834%, amr); Associated with Inborn genetic diseases.

What condition is associated with ASPM p.Pro226Ser (c.676C>T)?

ASPM p.Pro226Ser (c.676C>T) is associated with Inborn genetic diseases, microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Pro226Ser (c.676C>T) in the general population?

ASPM p.Pro226Ser (c.676C>T) is ultra-rare (popmax 0.0834%, amr) (gnomAD).

What do computational predictors say about ASPM p.Pro226Ser (c.676C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

ASPM p.Pro226Ser

c.676C>T · rs147830520 · VCV877003

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.134	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 8.6	GERP 0.89, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,369 bp · p 0.063 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0834% Admixed American · 50/59,986 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0584%

Overall 0.0158% 255/1,613,242 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0834%	1,200
Remaining individualsnot grpmax-eligible	0.0224%	4,462
European (non-Finnish)	0.0159%	6,276
Finnishnot grpmax-eligible	0.00315%	31,709
African / African-American	0.00134%	74,892

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.Pro226Ser
Coding: c.676C>T
MANE Select: NM_018136
dbSNP: rs147830520
Type: single nucleotide variant
Location: chr1:197143576 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly 5, primary, autosomal recessive

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-pro226ser (accessed [today's date]).

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