Is ASPM p.Thr2499fs (c.7491_7495del) pathogenic?

ASPM p.Thr2499fs (c.74917495del) is classified Pathogenic/Likely pathogenic in ASPM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-31). Very rare (popmax 0.00263%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ASPM p.Thr2499fs (c.7491_7495del)?

ASPM p.Thr2499fs (c.7491_7495del) is associated with Inborn genetic diseases, microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Thr2499fs (c.7491_7495del) in the general population?

ASPM p.Thr2499fs (c.7491_7495del) is very rare (popmax 0.00263%, nfe) (gnomAD).

ASPM p.Thr2499fs

c.7491_7495del · rs199422172 · VCV21600

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.036	GERP -3.6
Overall
CADD	24.2	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 0.00263% European (non-Finnish) · 31/1,179,138 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00205% 33/1,612,228 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,197
European (non-Finnish)grpmax	0.00263%	38,037

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.Thr2499fs
Coding: c.7491_7495del
MANE Select: NM_018136
dbSNP: rs199422172
Type: Deletion
Location: chr1:197101756 (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 p.Arg2005fs Pathogenic ★★ same condition
ASPM p.Asn1095fs Likely pathogenic ★★ same condition
ASPM p.Asn324fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Asn394fs Pathogenic ★★ same condition
ASPM p.Asp1285fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Asp990fs Pathogenic ★★ same condition
ASPM p.Gln2904fs Pathogenic ★★ same condition
ASPM p.Glu2731fs 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-thr2499fs (accessed [today's date]).

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