Is ASPM p.Ala1258= (c.3774A>G) pathogenic?

ASPM p.Ala1258= (c.3774A>G) is classified Uncertain significance in ASPM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). Very rare (popmax 0.0011%, sas).

How common is ASPM p.Ala1258= (c.3774A>G) in the general population?

ASPM p.Ala1258= (c.3774A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

ASPM p.Ala1258=

c.3774A>G · rs1231549951 · VCV2791585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.43	GERP -2.8, phastCons 0.013
Overall
CADD	7.458	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,046 alleles

Overall 0.000137% 2/1,460,298 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,444
South Asiangrpmax	0.0011%	91,046

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1258=
Coding: c.3774A>G
MANE Select: NM_018136
dbSNP: rs1231549951
Type: single nucleotide variant
Location: chr1:197122011 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1258: the calponin-homology (ch) 2 domain

Full ASPM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASPM p.Ala1258Thr Conflicting classifications of pathogenicity ★ same residue
ASPM c.2419+2T>C Pathogenic/Likely pathogenic ★★ same type
ASPM c.2488-1G>C Pathogenic/Likely pathogenic ★★ same type
ASPM c.2936+5G>A Likely pathogenic ★★ same type
ASPM c.3082+1G>C Pathogenic/Likely pathogenic ★★ same type
ASPM c.9084+5G>A Likely pathogenic ★★ same type
ASPM p.Arg1019Ter Pathogenic ★★ same type
ASPM p.Arg1271Ter Pathogenic ★★ same type

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-ala1258 (accessed [today's date]).

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