Is ASPM p.Arg1729Trp (c.5185C>T) pathogenic?

ASPM p.Arg1729Trp (c.5185C>T) is classified Benign/Likely benign in ASPM (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1397); Low-frequency (popmax 2.23%, mid); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg1729Trp (c.5185C>T)?

ASPM p.Arg1729Trp (c.5185C>T) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg1729Trp (c.5185C>T) in the general population?

ASPM p.Arg1729Trp (c.5185C>T) is low-frequency (popmax 2.23%, mid) (gnomAD).

What do computational predictors say about ASPM p.Arg1729Trp (c.5185C>T)?

AlphaMissense predicts likely benign (score 0.1397) — an in-silico prediction, not a clinical call.

ASPM p.Arg1729Trp

c.5185C>T · rs41299623 · VCV95889

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1397 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.23%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1397	likely benign
REVEL	0.279	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 1.6	GERP 0.89, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	24.4	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 2.23% Middle Eastern · 135/6,058 alleles

Filtering AF 1.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.81%

Overall 0.965% 15,564/1,612,828 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.23%	45
Ashkenazi Jewishnot grpmax-eligible	1.87%	53
South Asian	1.23%	81
Admixed American	1.19%	84
Remaining individualsnot grpmax-eligible	1.04%	96
European (non-Finnish)	1.03%	98
Finnishnot grpmax-eligible	0.262%	382
Amishnot grpmax-eligible	0.219%	456
African / African-American	0.149%	669
East Asian	0.0446%	2,241

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.Arg1729Trp
Coding: c.5185C>T
MANE Select: NM_018136
dbSNP: rs41299623
Type: single nucleotide variant
Location: chr1:197104066 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1729: the iq 6 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.Arg1729Gln Uncertain significance ★ ⚠ 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-arg1729trp (accessed [today's date]).

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