Is ASPM p.Ser1379Pro (c.4135T>C) pathogenic?

ASPM p.Ser1379Pro (c.4135T>C) is classified Uncertain significance in ASPM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.8039); Ultra-rare (popmax 0.0268%, afr); Associated with Inborn genetic diseases.

What condition is associated with ASPM p.Ser1379Pro (c.4135T>C)?

ASPM p.Ser1379Pro (c.4135T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ASPM p.Ser1379Pro (c.4135T>C) in the general population?

ASPM p.Ser1379Pro (c.4135T>C) is ultra-rare (popmax 0.0268%, afr) (gnomAD).

What do computational predictors say about ASPM p.Ser1379Pro (c.4135T>C)?

AlphaMissense predicts likely pathogenic (score 0.8039) — an in-silico prediction, not a clinical call.

ASPM p.Ser1379Pro

c.4135T>C · rs768625023 · VCV389374

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8039 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8039	likely pathogenic · top 4% in ASPM
REVEL	0.457	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.17, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0268% African / African-American · 20/74,726 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00124% 20/1,608,868 alleles · ultra-rare exomes 6/1,456,918 · genomes 14/151,950 · joint denominator

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.Ser1379Pro
Coding: c.4135T>C
MANE Select: NM_018136
dbSNP: rs768625023
Type: single nucleotide variant
Location: chr1:197105116 (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.Ser1379Tyr 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-ser1379pro (accessed [today's date]).

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