Is MCPH1 p.Ser89Ter (c.266C>G) pathogenic?

MCPH1 p.Ser89Ter (c.266C>G) is classified Likely pathogenic in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). Very rare (popmax 0.00017%, nfe); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Ser89Ter (c.266C>G)?

MCPH1 p.Ser89Ter (c.266C>G) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Ser89Ter (c.266C>G) in the general population?

MCPH1 p.Ser89Ter (c.266C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

MCPH1 p.Ser89Ter

c.266C>G · VCV3595788

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 14
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2.5, phastCons 0.22
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,706 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,346 alleles · very rare

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: MCPH1
Protein: p.Ser89Ter
Coding: c.266C>G
MANE Select: NM_024596
Type: single nucleotide variant
Location: chr8:6431531 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 89: the brct 1 domain; an α-helix

Full MCPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 1, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MCPH1 p.Ser89Leu Uncertain significance ★ ⚠ same residue
MCPH1 c.321+2T>C Likely pathogenic ★★ same condition
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Ser72Leu Pathogenic/Likely pathogenic ★★ same condition
MCPH1 c.1935+6T>C 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/mcph1-p-ser89ter (accessed [today's date]).

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