Is MCPH1 p.Arg187Ser (c.561G>T) pathogenic?

MCPH1 p.Arg187Ser (c.561G>T) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.8494); Rare (popmax 0.268%, eas); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Arg187Ser (c.561G>T)?

MCPH1 p.Arg187Ser (c.561G>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Arg187Ser (c.561G>T) in the general population?

MCPH1 p.Arg187Ser (c.561G>T) is rare (popmax 0.268%, eas) (gnomAD).

What do computational predictors say about MCPH1 p.Arg187Ser (c.561G>T)?

AlphaMissense predicts likely pathogenic (score 0.8494) — an in-silico prediction, not a clinical call.

MCPH1 p.Arg187Ser

c.561G>T · rs776125109 · VCV909076

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8494 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.268%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.8494	likely pathogenic · top 7% in MCPH1
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -2.1, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	21.1	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 0.268% East Asian · 120/44,832 alleles

Filtering AF 0.229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.00744% 120/1,613,182 alleles · rare exomes 116/1,461,076 · genomes 4/152,106 · joint denominator

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.Arg187Ser
Coding: c.561G>T
MANE Select: NM_024596
dbSNP: rs776125109
Type: single nucleotide variant
Location: chr8:6439077 (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.Arg187= Likely benign ★ 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-arg187ser (accessed [today's date]).

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