Is MCPH1 p.Ser709Phe (c.2126C>T) pathogenic?

MCPH1 p.Ser709Phe (c.2126C>T) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-25). AlphaMissense: likely pathogenic (0.7578); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Ser709Phe (c.2126C>T)?

MCPH1 p.Ser709Phe (c.2126C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MCPH1 p.Ser709Phe (c.2126C>T) in the general population?

MCPH1 p.Ser709Phe (c.2126C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Ser709Phe (c.2126C>T)?

AlphaMissense predicts likely pathogenic (score 0.7578) — an in-silico prediction, not a clinical call.

MCPH1 p.Ser709Phe

c.2126C>T · rs2129559816 · VCV1897917

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7578 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7578	likely pathogenic · top 10% in MCPH1
REVEL	0.642	indeterminate
SaProt	LLR -13.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	27.7	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 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,780 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000254%	393,345

Ashkenazi Jewish 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.Ser709Phe
Coding: c.2126C>T
MANE Select: NM_024596
dbSNP: rs2129559816
Type: single nucleotide variant
Location: chr8:6480866 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 709: the brct 2 domain; a β-strand

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

Similar variants

MCPH1 c.1935+6T>C Uncertain significance ★★ same condition
MCPH1 p.Ala401Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Ala404Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg373Thr Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg379Ile Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg703His Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg785Trp Uncertain significance ★★ ⚠ same condition
MCPH1 p.Asp758Asn Uncertain significance ★★ ⚠ same condition

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-ser709phe (accessed [today's date]).

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