Is ASPM p.Phe2735Val (c.8203T>G) pathogenic?

ASPM p.Phe2735Val (c.8203T>G) is classified Conflicting classifications of pathogenicity in ASPM (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1381); Low-frequency (popmax 1.31%, sas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Phe2735Val (c.8203T>G)?

ASPM p.Phe2735Val (c.8203T>G) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Phe2735Val (c.8203T>G) in the general population?

ASPM p.Phe2735Val (c.8203T>G) is low-frequency (popmax 1.31%, sas) (gnomAD).

What do computational predictors say about ASPM p.Phe2735Val (c.8203T>G)?

AlphaMissense predicts likely benign (score 0.1381) — an in-silico prediction, not a clinical call.

ASPM p.Phe2735Val

c.8203T>G · rs372416792 · VCV157890

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1381 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.31%, sas)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1381	likely benign
REVEL	0.303	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP 1.4
Regional constraint	o/e 1.01	unconstrained · MANE · 59 kb · p 0.59 · regional, not allelic
Overall
CADD	14.41	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 1.31% South Asian · 1,193/90,976 alleles

Filtering AF 1.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.22%

Overall 0.0793% 1,278/1,611,622 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.31%	76
Remaining individualsnot grpmax-eligible	0.119%	842
Middle Eastern	0.0332%	3,016
Admixed American	0.00503%	19,870
African / African-American	0.00401%	24,931
European (non-Finnish)	0.000254%	392,966

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.Phe2735Val
Coding: c.8203T>G
MANE Select: NM_018136
dbSNP: rs372416792
Type: single nucleotide variant
Location: chr1:197101048 (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

microcephaly 5, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPM p.Phe2735Ile Uncertain significance ★ ⚠ same residue
ASPM p.Phe2735Ser 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

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-phe2735val (accessed [today's date]).

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