Is APC2 p.Pro1325Ser (c.3973C>T) pathogenic?

APC2 p.Pro1325Ser (c.3973C>T) is classified Conflicting classifications of pathogenicity in APC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0896); Rare (popmax 0.46%, mid); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Pro1325Ser (c.3973C>T)?

APC2 p.Pro1325Ser (c.3973C>T) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Pro1325Ser (c.3973C>T) in the general population?

APC2 p.Pro1325Ser (c.3973C>T) is rare (popmax 0.46%, mid) (gnomAD).

What do computational predictors say about APC2 p.Pro1325Ser (c.3973C>T)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

APC2 p.Pro1325Ser

c.3973C>T · rs766720269 · VCV2038297

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.46%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.281	benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -1.3
Overall
CADD	6.326	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 0.46% Middle Eastern · 16/3,478 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.235%

Overall 0.0494% 647/1,308,682 alleles · rare exomes 580/1,156,738 · genomes 67/151,944 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.46%	217
Ashkenazi Jewishnot grpmax-eligible	0.115%	869
Admixed American	0.0831%	1,203
Remaining individualsnot grpmax-eligible	0.0766%	1,305
South Asian	0.0592%	1,690
European (non-Finnish)	0.0495%	2,019
African / African-American	0.0155%	6,471
Finnishnot grpmax-eligible	0.0081%	12,353

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.Pro1325Ser
Coding: c.3973C>T
MANE Select: NM_005883
dbSNP: rs766720269
Type: single nucleotide variant
Location: chr19:1467274 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1325: 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-pro1325ser (accessed [today's date]).

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