Is APC2 p.Ser1578Phe (c.4733C>T) pathogenic?

APC2 p.Ser1578Phe (c.4733C>T) is classified Uncertain significance in APC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.7311); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Ser1578Phe (c.4733C>T)?

APC2 p.Ser1578Phe (c.4733C>T) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Ser1578Phe (c.4733C>T) in the general population?

APC2 p.Ser1578Phe (c.4733C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about APC2 p.Ser1578Phe (c.4733C>T)?

AlphaMissense predicts likely pathogenic (score 0.7311) — an in-silico prediction, not a clinical call.

APC2 p.Ser1578Phe

c.4733C>T · VCV4122508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7311	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.74, phastCons 1
Overall
CADD	28.9	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 0.0167% Middle Eastern · 1/5,976 alleles

Overall 0.00021% 3/1,430,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,976
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,934
European (non-Finnish)	8.52e-05%	1,173,433

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: APC2
Protein: p.Ser1578Phe
Coding: c.4733C>T
MANE Select: NM_005883
Type: single nucleotide variant
Location: chr19:1468034 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1578: the '5 x 20 aa approximate repeat of f-x-v-e-x-t-p-x-c-f-s-r-x-s-s-l-s-s-l-s' region; the 'interaction with ctnnb1' region; the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

Full APC2 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

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1492Glu 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-ser1578phe (accessed [today's date]).

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