Is APC p.Pro2234Ser (c.6700C>T) pathogenic?

APC p.Pro2234Ser (c.6700C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.7891); Very rare (popmax 0.00246%, nfe); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.Pro2234Ser (c.6700C>T)?

APC p.Pro2234Ser (c.6700C>T) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro2234Ser (c.6700C>T) in the general population?

APC p.Pro2234Ser (c.6700C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about APC p.Pro2234Ser (c.6700C>T)?

AlphaMissense predicts likely pathogenic (score 0.7891) — an in-silico prediction, not a clinical call.

APC p.Pro2234Ser

c.6700C>T · rs749507584 · VCV185231

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.7891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.7891	likely pathogenic
REVEL	0.594	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	25.3	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 0.00246% European (non-Finnish) · 29/1,179,830 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00198% 32/1,613,730 alleles · very rare exomes 30/1,461,662 · genomes 2/152,068 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,822
European (non-Finnish)grpmax	0.00246%	40,684

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2234Ser
Coding: c.6700C>T
MANE Select: NM_000038
dbSNP: rs749507584
Type: single nucleotide variant
Location: chr5:112842294 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2234: the 'disordered' region; the 'basic region' region

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

Disease context

classic or attenuated familial adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Pro2234Ala Uncertain significance ★★ same residue
APC p.Pro2234Arg Uncertain significance ★ ⚠ same residue
APC p.Pro2234Leu Uncertain significance ★ ⚠ same residue
APC p.Pro2234= 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-pro2234ser (accessed [today's date]).

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