Is ASPM p.Arg1002His (c.3005G>A) pathogenic?

ASPM p.Arg1002His (c.3005G>A) is classified Uncertain significance in ASPM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-10). AlphaMissense: ambiguous (0.407); Ultra-rare (popmax 0.0174%, afr).

How common is ASPM p.Arg1002His (c.3005G>A) in the general population?

ASPM p.Arg1002His (c.3005G>A) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about ASPM p.Arg1002His (c.3005G>A)?

AlphaMissense predicts ambiguous (score 0.407) — an in-silico prediction, not a clinical call.

ASPM p.Arg1002His

c.3005G>A · rs749600804 · VCV1460642

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.407 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Computational evidence

Protein change
AlphaMissense	0.407	ambiguous
REVEL	0.412	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.91, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	28.1	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 0.0174% African / African-American · 13/74,890 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00204% 33/1,613,776 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
Admixed American	0.005%	19,999
South Asian	0.00439%	22,769
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0032%	31,236
East Asian	0.00223%	44,860
European (non-Finnish)	0.000763%	131,097

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.Arg1002His
Coding: c.3005G>A
MANE Select: NM_018136
dbSNP: rs749600804
Type: single nucleotide variant
Location: chr1:197125123 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1002: the calponin-homology (ch) 1 domain

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

Similar variants

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
ASPM p.Arg1392Ter 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-arg1002his (accessed [today's date]).

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