Is MCPH1 p.Ser287Arg (c.859A>C) pathogenic?

MCPH1 p.Ser287Arg (c.859A>C) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.1979); Ultra-rare (popmax 0.0786%, afr).

How common is MCPH1 p.Ser287Arg (c.859A>C) in the general population?

MCPH1 p.Ser287Arg (c.859A>C) is ultra-rare (popmax 0.0786%, afr) (gnomAD).

What do computational predictors say about MCPH1 p.Ser287Arg (c.859A>C)?

AlphaMissense predicts likely benign (score 0.1979) — an in-silico prediction, not a clinical call.

MCPH1 p.Ser287Arg

c.859A>C · rs149813931 · VCV596570

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0786%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1979	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -8.67	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 0.52	GERP -2.3
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	11.15	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 0.0786% African / African-American · 59/75,072 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.00421% 68/1,614,224 alleles · ultra-rare exomes 33/1,461,842 · genomes 35/152,382 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0786%	1,272
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00167%	60,030
South Asian	0.0011%	91,084
European (non-Finnish)	0.000254%	393,338

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.Ser287Arg
Coding: c.859A>C
MANE Select: NM_024596
dbSNP: rs149813931
Type: single nucleotide variant
Location: chr8:6444581 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 287: a modified residue (phosphoserine)

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

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MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same type
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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-ser287arg (accessed [today's date]).

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