Is ASPM p.Arg2332Ter (c.6994C>T) pathogenic?

ASPM p.Arg2332Ter (c.6994C>T) is classified Pathogenic in ASPM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-24). Very rare (popmax 0.0011%, sas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg2332Ter (c.6994C>T)?

ASPM p.Arg2332Ter (c.6994C>T) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg2332Ter (c.6994C>T) in the general population?

ASPM p.Arg2332Ter (c.6994C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

ASPM p.Arg2332Ter

c.6994C>T · rs1451306414 · VCV1029675

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 28
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.028, phastCons 0.12
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,052 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,460,846 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,052
European (non-Finnish)	0.000933%	107,204

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.Arg2332Ter
Coding: c.6994C>T
MANE Select: NM_018136
dbSNP: rs1451306414
Type: single nucleotide variant
Location: chr1:197102257 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2332: the iq 22 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-arg2332ter (accessed [today's date]).

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