Is APC p.Pro865Ser (c.2593C>T) pathogenic?

APC p.Pro865Ser (c.2593C>T) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-08-13). AlphaMissense: likely benign (0.0726); Rare (popmax 0.115%, mid); Associated with Gardner syndrome.

What condition is associated with APC p.Pro865Ser (c.2593C>T)?

APC p.Pro865Ser (c.2593C>T) is associated with Gardner syndrome, hereditary neoplastic syndrome, APC-related attenuated familial adenomatous polyposis (ClinVar).

How common is APC p.Pro865Ser (c.2593C>T) in the general population?

APC p.Pro865Ser (c.2593C>T) is rare (popmax 0.115%, mid) (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APC p.Pro865Ser (c.2593C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

APC p.Pro865Ser

c.2593C>T · rs192620988 · VCV135690

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Gardner syndrome

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.021	GERP -0.75, phastCons 0.005
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.00942% 152/1,614,166 alleles · rare exomes 110/1,461,880 · genomes 42/152,286 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,850
Admixed American	0.0433%	2,309
African / African-American	0.0373%	2,680
Remaining individualsnot grpmax-eligible	0.0352%	2,841
South Asian	0.00549%	18,215
European (non-Finnish)	0.00407%	24,584

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: APC
Protein: p.Pro865Ser
Coding: c.2593C>T
MANE Select: NM_000038
dbSNP: rs192620988
Type: single nucleotide variant
Location: chr5:112838187 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 865: the 'disordered' region

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

Disease context

Gardner syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome APC-related attenuated familial adenomatous polyposis classic familial adenomatous polyposis familial adenomatous polyposis 1

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Pro865Ala Uncertain significance ★★ ⚠ same residue
APC p.Pro865Leu Uncertain significance ★ same residue
APC p.Pro865Thr Uncertain significance ★ ⚠ same residue
APC p.Pro865= Likely benign ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G Pathogenic ★★★ same condition
APC c.1312+5G>A Likely pathogenic ★★★ same condition
APC c.1312+5G>C Likely pathogenic ★★★ 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/apc-p-pro865ser (accessed [today's date]).

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