Is ASPM p.Arg2743Gln (c.8228G>A) pathogenic?

ASPM p.Arg2743Gln (c.8228G>A) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.0809); Rare (popmax 0.21%, eas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg2743Gln (c.8228G>A)?

ASPM p.Arg2743Gln (c.8228G>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg2743Gln (c.8228G>A) in the general population?

ASPM p.Arg2743Gln (c.8228G>A) is rare (popmax 0.21%, eas) (gnomAD).

What do computational predictors say about ASPM p.Arg2743Gln (c.8228G>A)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

ASPM p.Arg2743Gln

c.8228G>A · rs202193200 · VCV194878

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.21%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.129	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.3	GERP -3.2
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	16.63	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 0.21% East Asian · 94/44,726 alleles

Filtering AF 0.176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.163%

Overall 0.00955% 154/1,612,122 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.21%	476
Remaining individualsnot grpmax-eligible	0.0337%	2,971
African / African-American	0.0107%	9,361
European (non-Finnish)	0.00237%	42,107
South Asian	0.0022%	45,511
Admixed American	0.00167%	59,726

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.Arg2743Gln
Coding: c.8228G>A
MANE Select: NM_018136
dbSNP: rs202193200
Type: single nucleotide variant
Location: chr1:197101023 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2743: the iq 31 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.Arg2743Ter Pathogenic ★ same residue
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

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-arg2743gln (accessed [today's date]).

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