Is ASPM p.Leu972Val (c.2914T>G) pathogenic?

ASPM p.Leu972Val (c.2914T>G) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.3828); Rare (popmax 0.252%, amr); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Leu972Val (c.2914T>G)?

ASPM p.Leu972Val (c.2914T>G) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Leu972Val (c.2914T>G) in the general population?

ASPM p.Leu972Val (c.2914T>G) is rare (popmax 0.252%, amr) (gnomAD).

What do computational predictors say about ASPM p.Leu972Val (c.2914T>G)?

AlphaMissense predicts ambiguous (score 0.3828) — an in-silico prediction, not a clinical call.

ASPM p.Leu972Val

c.2914T>G · rs552158003 · VCV157798

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3828 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.252%, amr)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.3828	ambiguous
REVEL	0.797	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	22.2	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 0.252% Admixed American · 151/60,018 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.206%

Overall 0.00961% 155/1,613,682 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.252%	397
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Leu972Val
Coding: c.2914T>G
MANE Select: NM_018136
dbSNP: rs552158003
Type: single nucleotide variant
Location: chr1:197128512 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 972: the calponin-homology (ch) 1 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.Leu972= 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-leu972val (accessed [today's date]).

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