Is MCPH1 p.Arg752His (c.2255G>A) pathogenic?

MCPH1 p.Arg752His (c.2255G>A) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-26). AlphaMissense: likely benign (0.0885); Ultra-rare (popmax 0.0133%, afr).

How common is MCPH1 p.Arg752His (c.2255G>A) in the general population?

MCPH1 p.Arg752His (c.2255G>A) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about MCPH1 p.Arg752His (c.2255G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

MCPH1 p.Arg752His

c.2255G>A · rs536823455 · VCV1256318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.55	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 -3.1	GERP -4.1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	0.346	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 0.0133% African / African-American · 10/75,054 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00124% 20/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,505
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,504
South Asian	0.0011%	91,076
European (non-Finnish)	0.000508%	196,670

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.Arg752His
Coding: c.2255G>A
MANE Select: NM_024596
dbSNP: rs536823455
Type: single nucleotide variant
Location: chr8:6621494 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 752: the brct 3 domain

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

Similar variants

MCPH1 p.Arg752Gly Uncertain significance ★★ ⚠ same residue
MCPH1 p.Arg752= Benign/Likely benign ★★ same residue
MCPH1 c.321+2T>C Likely pathogenic ★★ same type
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gln199Ter Pathogenic ★★ same type
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same type

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-arg752his (accessed [today's date]).

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