Is MCPH1 p.Leu730Gln (c.2189T>A) pathogenic?

MCPH1 p.Leu730Gln (c.2189T>A) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-08). AlphaMissense: ambiguous (0.4394); Very rare (popmax 0.00254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Leu730Gln (c.2189T>A)?

MCPH1 p.Leu730Gln (c.2189T>A) is associated with Inborn genetic diseases (ClinVar).

How common is MCPH1 p.Leu730Gln (c.2189T>A) in the general population?

MCPH1 p.Leu730Gln (c.2189T>A) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Leu730Gln (c.2189T>A)?

AlphaMissense predicts ambiguous (score 0.4394) — an in-silico prediction, not a clinical call.

MCPH1 p.Leu730Gln

c.2189T>A · rs771694886 · VCV1502904

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4394	ambiguous
REVEL	0.47	indeterminate
SaProt	LLR -12.00	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	23.5	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 0.00254% European (non-Finnish) · 30/1,179,988 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,613,628 alleles · very rare exomes 29/1,461,404 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,333
Remaining individualsnot grpmax-eligible	0.0016%	62,436

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.Leu730Gln
Coding: c.2189T>A
MANE Select: NM_024596
dbSNP: rs771694886
Type: single nucleotide variant
Location: chr8:6499904 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-leu730gln (accessed [today's date]).

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