Is MCPH1 p.Pro436fs (c.1305_1315del) pathogenic?

MCPH1 p.Pro436fs (c.13051315del) is classified Likely pathogenic in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-14). Very rare (popmax 8.47e-05%, nfe); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Pro436fs (c.1305_1315del)?

MCPH1 p.Pro436fs (c.1305_1315del) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Pro436fs (c.1305_1315del) in the general population?

MCPH1 p.Pro436fs (c.1305_1315del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MCPH1 p.Pro436fs

c.1305_1315del · VCV3595794

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.1	GERP -3.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.84e-05% 1/1,461,888 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.Pro436fs
Coding: c.1305_1315del
MANE Select: NM_024596
Type: Deletion
Location: chr8:6445027 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 436: the 'disordered' region

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.Lys107fs Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Lys26fs Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Ser191fs Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Ser623_Cys624insTer Pathogenic/Likely pathogenic ★★ same condition
MCPH1 c.1935+1_1935+5del Likely pathogenic ★ same condition
MCPH1 c.22+2_22+4del Pathogenic ★ same condition
MCPH1 p.Arg469fs Likely pathogenic ★ same condition
MCPH1 p.Asp668fs Likely 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/mcph1-p-pro436fs (accessed [today's date]).

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