Is ASPM p.Ser2284Phe (c.6851C>T) pathogenic?

ASPM p.Ser2284Phe (c.6851C>T) is classified Uncertain significance in ASPM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-08). AlphaMissense: likely benign (0.146); Ultra-rare (popmax 0.0441%, afr); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Ser2284Phe (c.6851C>T)?

ASPM p.Ser2284Phe (c.6851C>T) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Ser2284Phe (c.6851C>T) in the general population?

ASPM p.Ser2284Phe (c.6851C>T) is ultra-rare (popmax 0.0441%, afr) (gnomAD).

What do computational predictors say about ASPM p.Ser2284Phe (c.6851C>T)?

AlphaMissense predicts likely benign (score 0.146) — an in-silico prediction, not a clinical call.

ASPM p.Ser2284Phe

c.6851C>T · rs371321801 · VCV1678770

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0441%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.146	likely benign
REVEL	0.26	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 0.013
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0441% African / African-American · 33/74,794 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0282%

Overall 0.0031% 50/1,612,616 alleles · ultra-rare exomes 32/1,460,838 · genomes 18/151,778 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0441%	2,266
Admixed American	0.0134%	7,470
Finnishnot grpmax-eligible	0.011%	9,129
Remaining individualsnot grpmax-eligible	0.0032%	31,215

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.Ser2284Phe
Coding: c.6851C>T
MANE Select: NM_018136
dbSNP: rs371321801
Type: single nucleotide variant
Location: chr1:197102400 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2284: the iq 21 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.Ser2284Thr Uncertain significance ★ ⚠ same residue
ASPM p.Ser2284= 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-ser2284phe (accessed [today's date]).

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