Is MCPH1 p.Pro727= (c.2181G>A) pathogenic?

MCPH1 p.Pro727= (c.2181G>A) is classified Likely benign in MCPH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-01). Ultra-rare (popmax 0.0175%, mid).

How common is MCPH1 p.Pro727= (c.2181G>A) in the general population?

MCPH1 p.Pro727= (c.2181G>A) is ultra-rare (popmax 0.0175%, mid) (gnomAD).

MCPH1 p.Pro727=

c.2181G>A · rs774188140 · VCV3003253

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, mid)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -9.2	GERP -3.9
Overall
CADD	0.161	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% Middle Eastern · 1/5,702 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,504 alleles · ultra-rare exomes 24/1,461,316 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0175%	5,702
East Asian	0.00223%	44,884
European (non-Finnish)	0.00178%	56,190
Admixed American	0.00167%	59,992
South Asian	0.0011%	91,066

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.Pro727=
Coding: c.2181G>A
MANE Select: NM_024596
dbSNP: rs774188140
Type: single nucleotide variant
Location: chr8:6499896 (GRCh38)

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

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-pro727 (accessed [today's date]).

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