Is MCPH1 p.Pro520Ala (c.1558C>G) pathogenic?

MCPH1 p.Pro520Ala (c.1558C>G) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely benign (0.0726); Very rare (popmax 0.000169%, nfe).

How common is MCPH1 p.Pro520Ala (c.1558C>G) in the general population?

MCPH1 p.Pro520Ala (c.1558C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Pro520Ala (c.1558C>G)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

MCPH1 p.Pro520Ala

c.1558C>G · rs2486156430 · VCV2429702

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.81	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 -0.4	GERP -3.6
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	6.788	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 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,862 alleles · very rare

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.Pro520Ala
Coding: c.1558C>G
MANE Select: NM_024596
dbSNP: rs2486156430
Type: single nucleotide variant
Location: chr8:6445280 (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

Similar variants

MCPH1 p.Pro520= 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
MCPH1 p.Lys105Ter 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-pro520ala (accessed [today's date]).

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