Is APC p.Arg259= (c.777G>T) pathogenic?

APC p.Arg259= (c.777G>T) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-05-01). Very rare (popmax 0.00305%, nfe); Associated with APC-Associated Polyposis Disorders.

What condition is associated with APC p.Arg259= (c.777G>T)?

APC p.Arg259= (c.777G>T) is associated with APC-Associated Polyposis Disorders, colon carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Arg259= (c.777G>T) in the general population?

APC p.Arg259= (c.777G>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

APC p.Arg259=

c.777G>T · rs147704593 · VCV135720

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Conditions

APC-Associated Polyposis Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.87, phastCons 1
Overall
CADD	8.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00305% European (non-Finnish) · 36/1,179,208 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0162% 261/1,612,850 alleles · very rare exomes 235/1,460,686 · genomes 26/152,164 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.633%	158
Remaining individualsnot grpmax-eligible	0.0577%	1,734
European (non-Finnish)grpmax	0.00305%	32,756
Admixed American	0.00167%	59,946
African / African-American	0.00134%	74,880

Ashkenazi Jewish 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.Arg259=
Coding: c.777G>T
MANE Select: NM_000038
dbSNP: rs147704593
Type: single nucleotide variant
Location: chr5:112801326 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 259: the 'disordered' region

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

Disease context

APC-Associated Polyposis Disorders

Also linked: colon carcinoma hereditary neoplastic syndrome familial adenomatous polyposis 1 classic or attenuated familial adenomatous polyposis

Similar variants

APC p.Arg259Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
APC p.Arg259Trp Conflicting classifications of pathogenicity ★ same residue
APC p.Arg259fs Pathogenic ★ 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
APC c.1409-3T>G 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-arg259 (accessed [today's date]).

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