Is ASPM p.Ile2113fs (c.6337_6338del) pathogenic?

ASPM p.Ile2113fs (c.63376338del) is classified Pathogenic in ASPM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-09-21). Very rare (popmax 0.0011%, nfe); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ile2113fs (c.6337_6338del)?

ASPM p.Ile2113fs (c.6337_6338del) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ile2113fs (c.6337_6338del) in the general population?

ASPM p.Ile2113fs (c.6337_6338del) is very rare (popmax 0.0011%, nfe) (gnomAD).

ASPM p.Ile2113fs

c.6337_6338del · rs199422169 · VCV265381

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

microcephaly 5, primary, autosomal recessive

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 1.2	GERP -1, phastCons 0.67
Overall
CADD	24.7	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% European (non-Finnish) · 13/1,179,268 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000868% 14/1,612,604 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)grpmax	0.0011%	90,713

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.Ile2113fs
Coding: c.6337_6338del
MANE Select: NM_018136
dbSNP: rs199422169
Type: Microsatellite
Location: chr1:197102913 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2113: the iq 16 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 p.Arg1315fs Pathogenic ★★ same condition
ASPM p.Arg1416_Tyr1417insTer Pathogenic ★★ same condition
ASPM p.Arg1576fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Arg2229fs Pathogenic ★★ same condition
ASPM p.Asn653fs Pathogenic ★★ same condition
ASPM p.Gln2836fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Glu385fs Pathogenic ★★ same condition
ASPM p.Leu1864fs Pathogenic/Likely 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-ile2113fs (accessed [today's date]).

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