Is MCPH1 p.Ser347Ter (c.1040C>A) pathogenic?

MCPH1 p.Ser347Ter (c.1040C>A) is classified Pathogenic in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-27). Ultra-rare (popmax 0.0165%, mid).

How common is MCPH1 p.Ser347Ter (c.1040C>A) in the general population?

MCPH1 p.Ser347Ter (c.1040C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

MCPH1 p.Ser347Ter

c.1040C>A · rs1804028189 · VCV1071403

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 14
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.8
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,066 alleles · ultra-rare exomes 1/1,461,776 · genomes 0/152,290 · joint denominator

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.Ser347Ter
Coding: c.1040C>A
MANE Select: NM_024596
dbSNP: rs1804028189
Type: single nucleotide variant
Location: chr8:6444762 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 347: the 'disordered' region

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

Similar variants

MCPH1 c.321+2T>C Likely pathogenic ★★ same type
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gln199Ter Pathogenic ★★ same type
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Lys105Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Ser233Ter Pathogenic ★★ same type

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-ser347ter (accessed [today's date]).

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