Is MCPH1 p.Ile587Val (c.1759A>G) pathogenic?

MCPH1 p.Ile587Val (c.1759A>G) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0616); Rare (popmax 0.105%, eas).

How common is MCPH1 p.Ile587Val (c.1759A>G) in the general population?

MCPH1 p.Ile587Val (c.1759A>G) is rare (popmax 0.105%, eas) (gnomAD).

What do computational predictors say about MCPH1 p.Ile587Val (c.1759A>G)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

MCPH1 p.Ile587Val

c.1759A>G · rs372378731 · VCV379929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -5.71	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	GERP -3.3
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	0.159	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 0.105% East Asian · 47/44,886 alleles

Filtering AF 0.0808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0725%

Overall 0.0088% 142/1,614,066 alleles · rare exomes 107/1,461,680 · genomes 35/152,386 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	955
Remaining individualsnot grpmax-eligible	0.0736%	1,359
African / African-American	0.0346%	2,886
South Asian	0.0022%	45,538
European (non-Finnish)	0.00169%	59,001
Admixed American	0.00167%	59,982

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.Ile587Val
Coding: c.1759A>G
MANE Select: NM_024596
dbSNP: rs372378731
Type: single nucleotide variant
Location: chr8:6445481 (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 c.321+2T>C Likely pathogenic ★★ same type
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
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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
MCPH1 p.Ser233Ter 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-ile587val (accessed [today's date]).

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