Is APC2 p.Ser246Ter (c.737C>A) pathogenic?

APC2 p.Ser246Ter (c.737C>A) is classified Pathogenic in APC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-26). No allele count reported in gnomAD v4.1 (AN 1,608,638); Associated with cortical dysplasia, complex, with other brain malformations 10.

What condition is associated with APC2 p.Ser246Ter (c.737C>A)?

APC2 p.Ser246Ter (c.737C>A) is associated with cortical dysplasia, complex, with other brain malformations 10 (ClinVar).

How common is APC2 p.Ser246Ter (c.737C>A) in the general population?

APC2 p.Ser246Ter (c.737C>A) is no allele count reported in gnomAD v4.1 (AN 1,608,638) (gnomAD).

APC2 p.Ser246Ter

c.737C>A · rs1599137041 · VCV694622

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,608,638)

Conditions

cortical dysplasia, complex, with other brain malformations 10

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 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.2, phastCons 0.99
Overall
CADD	38.0	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

No allele count reported in gnomAD v4.1 (AN 1,608,638). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APC2
Protein: p.Ser246Ter
Coding: c.737C>A
MANE Select: NM_005883
dbSNP: rs1599137041
Type: single nucleotide variant
Location: chr19:1456325 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 246: a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cortical dysplasia, complex, with other brain malformations 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APC2 p.Ala1703Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala791Val Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1081Gly Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1539Pro Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1650His Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1708Leu Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1511Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1958Arg 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/apc2-p-ser246ter (accessed [today's date]).

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