Is MCPH1 p.Ser159= (c.477A>T) pathogenic?

MCPH1 p.Ser159= (c.477A>T) is classified Conflicting classifications of pathogenicity in MCPH1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-05-01). Rare (popmax 0.526%, nfe); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Ser159= (c.477A>T)?

MCPH1 p.Ser159= (c.477A>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Ser159= (c.477A>T) in the general population?

MCPH1 p.Ser159= (c.477A>T) is rare (popmax 0.526%, nfe) (gnomAD).

MCPH1 p.Ser159=

c.477A>T · rs41313948 · VCV158870

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.526%, nfe)

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 -9.9	GERP -3.6
Overall
CADD	0.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.526% European (non-Finnish) · 6,191/1,177,504 alleles

Filtering AF 0.515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.51%

Overall 0.428% 6,893/1,611,144 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.526%	190
Remaining individualsnot grpmax-eligible	0.407%	246
Ashkenazi Jewishnot grpmax-eligible	0.297%	336
Finnishnot grpmax-eligible	0.232%	431
Admixed American	0.205%	488
Middle Eastern	0.0991%	1,009
African / African-American	0.084%	1,190
South Asian	0.022%	4,552

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.Ser159=
Coding: c.477A>T
MANE Select: NM_024596
dbSNP: rs41313948
Type: single nucleotide variant
Location: chr8:6438993 (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 p.Ser159_Leu160insTer Pathogenic ★ 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-ser159 (accessed [today's date]).

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