Is ASPM p.Arg1046= (c.3138G>A) pathogenic?

ASPM p.Arg1046= (c.3138G>A) is classified Benign in ASPM (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-02). Common (popmax 34.7%, mid) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg1046= (c.3138G>A)?

ASPM p.Arg1046= (c.3138G>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

ASPM p.Arg1046=

Q: How common is ASPM p.Arg1046= (c.3138G>A) in the general population?

ASPM p.Arg1046= (c.3138G>A) is common (popmax 34.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3138G>A · rs6676084 · VCV21573

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 34.7%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.4
Overall
CADD	0.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.7% Middle Eastern · 1,981/5,714 alleles

Filtering AF 33.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.9%

Overall 29.5% 473,425/1,606,914 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	48.6%	2
Middle Easterngrpmax	34.7%	3
Finnishnot grpmax-eligible	31.8%	3
Ashkenazi Jewishnot grpmax-eligible	31.4%	3
European (non-Finnish)	30.9%	3
South Asian	30.7%	3
Remaining individualsnot grpmax-eligible	28.6%	3
Admixed American	24.9%	4
African / African-American	15.8%	6
East Asian	14.1%	7

Amish 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.Arg1046=
Coding: c.3138G>A
MANE Select: NM_018136
dbSNP: rs6676084
Type: single nucleotide variant
Location: chr1:197124900 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1046: the calponin-homology (ch) 1 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-arg1046 (accessed [today's date]).

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