Is ASPM p.Ala663Val (c.1988C>T) pathogenic?

ASPM p.Ala663Val (c.1988C>T) is classified Uncertain significance in ASPM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: ambiguous (0.465); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with ASPM p.Ala663Val (c.1988C>T)?

ASPM p.Ala663Val (c.1988C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ASPM p.Ala663Val (c.1988C>T) in the general population?

ASPM p.Ala663Val (c.1988C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ASPM p.Ala663Val (c.1988C>T)?

AlphaMissense predicts ambiguous (score 0.465) — an in-silico prediction, not a clinical call.

ASPM p.Ala663Val

c.1988C>T · VCV3790572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.465 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.465	ambiguous
REVEL	0.133	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	22.0	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 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000343% 5/1,459,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
African / African-American	0.00133%	74,998
European (non-Finnish)	0.000255%	392,741

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.Ala663Val
Coding: c.1988C>T
MANE Select: NM_018136
Type: single nucleotide variant
Location: chr1:197139805 (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

Similar variants

ASPM p.Ala663= Likely benign ★★ same residue
ASPM p.Ala663Ser Benign/Likely benign ★★ 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

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-ala663val (accessed [today's date]).

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