Is MCPH1 p.Ser765Trp (c.2294C>G) pathogenic?

MCPH1 p.Ser765Trp (c.2294C>G) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-21). AlphaMissense: likely pathogenic (0.5918); Ultra-rare (popmax 0.0247%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Ser765Trp (c.2294C>G)?

MCPH1 p.Ser765Trp (c.2294C>G) is associated with Inborn genetic diseases, microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Ser765Trp (c.2294C>G) in the general population?

MCPH1 p.Ser765Trp (c.2294C>G) is ultra-rare (popmax 0.0247%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Ser765Trp (c.2294C>G)?

AlphaMissense predicts likely pathogenic (score 0.5918) — an in-silico prediction, not a clinical call.

MCPH1 p.Ser765Trp

c.2294C>G · rs200820759 · VCV363562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.5918	likely pathogenic
REVEL	0.429	indeterminate
SaProt	LLR -14.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.6	GERP 1.1, phastCons 0.002
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0247% European (non-Finnish) · 292/1,180,042 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0211% 341/1,614,218 alleles · ultra-rare exomes 300/1,461,856 · genomes 41/152,362 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0281%	3,557
European (non-Finnish)grpmax	0.0247%	4,041
African / African-American	0.0213%	4,692
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,935
Remaining individualsnot grpmax-eligible	0.0144%	6,945

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser765Trp
Coding: c.2294C>G
MANE Select: NM_024596
dbSNP: rs200820759
Type: single nucleotide variant
Location: chr8:6621533 (GRCh38)

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

Also linked: microcephaly 1, primary, autosomal recessive

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-ser765trp (accessed [today's date]).

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