Is MCPH1 p.Ser595= (c.1785T>C) pathogenic?

MCPH1 p.Ser595= (c.1785T>C) is classified Conflicting classifications of pathogenicity in MCPH1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). Rare (popmax 0.133%, mid); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Ser595= (c.1785T>C)?

MCPH1 p.Ser595= (c.1785T>C) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Ser595= (c.1785T>C) in the general population?

MCPH1 p.Ser595= (c.1785T>C) is rare (popmax 0.133%, mid) (gnomAD).

MCPH1 p.Ser595=

c.1785T>C · rs146744659 · VCV435832

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.133%, mid)

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.3
Overall
CADD	0.522	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.133% Middle Eastern · 8/6,024 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0503%

Overall 0.0443% 713/1,609,816 alleles · rare exomes 653/1,457,438 · genomes 60/152,378 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.133%	753
European (non-Finnish)	0.0553%	1,808
Admixed American	0.0253%	3,948
Remaining individualsnot grpmax-eligible	0.0177%	5,660
South Asian	0.0156%	6,430
African / African-American	0.0147%	6,788
Finnishnot grpmax-eligible	0.00314%	31,843

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.Ser595=
Coding: c.1785T>C
MANE Select: NM_024596
dbSNP: rs146744659
Type: single nucleotide variant
Location: chr8:6445507 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB

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 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
MCPH1 p.Ala702Val 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-ser595 (accessed [today's date]).

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