Is ASPM p.Arg2665Cys (c.7993C>T) pathogenic?

ASPM p.Arg2665Cys (c.7993C>T) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.1306); Ultra-rare (popmax 0.0179%, eas); Associated with Inborn genetic diseases.

What condition is associated with ASPM p.Arg2665Cys (c.7993C>T)?

ASPM p.Arg2665Cys (c.7993C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ASPM p.Arg2665Cys (c.7993C>T) in the general population?

ASPM p.Arg2665Cys (c.7993C>T) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about ASPM p.Arg2665Cys (c.7993C>T)?

AlphaMissense predicts likely benign (score 0.1306) — an in-silico prediction, not a clinical call.

ASPM p.Arg2665Cys

c.7993C>T · rs201881549 · VCV1658405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1306 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1306	likely benign
REVEL	0.263	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 -0.33	GERP -2.1
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	16.73	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 0.0179% East Asian · 8/44,746 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00643%

Overall 0.00211% 34/1,611,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,593
Admixed American	0.0117%	8,528
South Asian	0.00769%	13,002
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,532
Remaining individualsnot grpmax-eligible	0.00321%	31,172
Finnishnot grpmax-eligible	0.00157%	63,892
European (non-Finnish)	0.000679%	147,316

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.Arg2665Cys
Coding: c.7993C>T
MANE Select: NM_018136
dbSNP: rs201881549
Type: single nucleotide variant
Location: chr1:197101258 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2665: the iq 29 domain

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

Similar variants

ASPM p.Arg2665His Uncertain significance ★ ⚠ same residue
ASPM p.Arg3304Ter Pathogenic ★★ same condition
ASPM p.Arg3390Ter Pathogenic ★★ same condition
ASPM p.Gln3060Ter Pathogenic ★★ same condition
ASPM p.Gln3321Ter Pathogenic ★★ same condition
ASPM p.Trp989Ter Pathogenic ★★ same condition
ASPM p.Ala1125Val Uncertain significance ★★ ⚠ same condition
ASPM p.Ala1319Ser Uncertain significance ★★ ⚠ 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-arg2665cys (accessed [today's date]).

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