Is MCPH1 p.Pro735Ser (c.2203C>T) pathogenic?

MCPH1 p.Pro735Ser (c.2203C>T) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-12). AlphaMissense: ambiguous (0.4518); Very rare (popmax 0.00644%, nfe).

How common is MCPH1 p.Pro735Ser (c.2203C>T) in the general population?

MCPH1 p.Pro735Ser (c.2203C>T) is very rare (popmax 0.00644%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Pro735Ser (c.2203C>T)?

AlphaMissense predicts ambiguous (score 0.4518) — an in-silico prediction, not a clinical call.

MCPH1 p.Pro735Ser

c.2203C>T · rs377727146 · VCV1903763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4518	ambiguous
REVEL	0.376	indeterminate
SaProt	LLR -10.72	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00644% European (non-Finnish) · 76/1,179,842 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.0049% 79/1,613,476 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00644%	15,524
Remaining individualsnot grpmax-eligible	0.0032%	31,225
South Asian	0.0011%	91,062

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.Pro735Ser
Coding: c.2203C>T
MANE Select: NM_001118887 · reported on NM_024596
dbSNP: rs377727146
Type: single nucleotide variant
Location: chr8:6499918 (GRCh38)

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

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-pro735ser (accessed [today's date]).

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