Is ASPM p.Thr336Lys (c.1007C>A) pathogenic?

ASPM p.Thr336Lys (c.1007C>A) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1074); Low-frequency (popmax 1.8%, eas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Thr336Lys (c.1007C>A)?

ASPM p.Thr336Lys (c.1007C>A) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Thr336Lys (c.1007C>A) in the general population?

ASPM p.Thr336Lys (c.1007C>A) is low-frequency (popmax 1.8%, eas) (gnomAD).

What do computational predictors say about ASPM p.Thr336Lys (c.1007C>A)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

ASPM p.Thr336Lys

c.1007C>A · rs112113370 · VCV157769

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.8%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.012	strongly 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 1.3	GERP 0.91, phastCons 0.001
Regional constraint	o/e 1.09	unconstrained · MANE · 3,369 bp · p 0.063 · regional, not allelic
Overall
CADD	0.804	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 1.8% East Asian · 808/44,828 alleles

Filtering AF 1.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.66%

Overall 0.0591% 953/1,612,252 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.8%	55
African / African-American	0.107%	937
Remaining individualsnot grpmax-eligible	0.0737%	1,357
Middle Eastern	0.0165%	6,056
South Asian	0.0154%	6,500
Admixed American	0.005%	19,990
European (non-Finnish)	8.48e-05%	1,178,552

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.Thr336Lys
Coding: c.1007C>A
MANE Select: NM_018136
dbSNP: rs112113370
Type: single nucleotide variant
Location: chr1:197143245 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 336: the 'sufficient for interaction with katna1:katnb1' region

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.Thr336= Likely benign ★ same residue
ASPM p.Thr336Ala Likely benign ★ 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

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-thr336lys (accessed [today's date]).

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