Is MCPH1 p.Pro750Arg (c.2249C>G) pathogenic?

MCPH1 p.Pro750Arg (c.2249C>G) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.0658); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Pro750Arg (c.2249C>G)?

MCPH1 p.Pro750Arg (c.2249C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MCPH1 p.Pro750Arg (c.2249C>G) in the general population?

MCPH1 p.Pro750Arg (c.2249C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MCPH1 p.Pro750Arg (c.2249C>G)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

MCPH1 p.Pro750Arg

c.2249C>G · rs765181940 · VCV2369795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -4.1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	0.028	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,614,004 alleles · very rare exomes 13/1,461,802 · genomes 4/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.00127%	78,668

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.Pro750Arg
Coding: c.2249C>G
MANE Select: NM_024596
dbSNP: rs765181940
Type: single nucleotide variant
Location: chr8:6621488 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 750: a β-strand

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

Similar variants

MCPH1 p.Pro750= Likely benign ★ same residue
MCPH1 c.1935+6T>C Uncertain significance ★★ same condition
MCPH1 p.Ala401Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Ala404Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg373Thr Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg379Ile Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg703His Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg785Trp 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-pro750arg (accessed [today's date]).

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