Is MCPH1 p.Ala702Ser (c.2104G>T) pathogenic?

MCPH1 p.Ala702Ser (c.2104G>T) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.1679); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Ala702Ser (c.2104G>T)?

MCPH1 p.Ala702Ser (c.2104G>T) is associated with Inborn genetic diseases (ClinVar).

How common is MCPH1 p.Ala702Ser (c.2104G>T) in the general population?

MCPH1 p.Ala702Ser (c.2104G>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Ala702Ser (c.2104G>T)?

AlphaMissense predicts likely benign (score 0.1679) — an in-silico prediction, not a clinical call.

MCPH1 p.Ala702Ser

c.2104G>T · rs377336996 · VCV3124469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1679	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.85, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	22.2	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 0.0011% European (non-Finnish) · 13/1,180,048 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,878 alleles · very rare

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.Ala702Ser
Coding: c.2104G>T
MANE Select: NM_024596
dbSNP: rs377336996
Type: single nucleotide variant
Location: chr8:6480844 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 702: the brct 2 domain; an α-helix

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 p.Ala702Val Uncertain significance ★★ ⚠ same residue
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

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-ala702ser (accessed [today's date]).

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