Is APC p.Arg653= (c.1959G>A) pathogenic?

APC p.Arg653= (c.1959G>A) is classified Benign/Likely benign in APC (ClinVar, Multiple submitters, 30 submitters; last evaluated 2026-05-01). Rare (popmax 0.374%, nfe); Associated with APC-Associated Polyposis Disorders.

What condition is associated with APC p.Arg653= (c.1959G>A)?

APC p.Arg653= (c.1959G>A) is associated with APC-Associated Polyposis Disorders, colon carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Arg653= (c.1959G>A) in the general population?

APC p.Arg653= (c.1959G>A) is rare (popmax 0.374%, nfe) (gnomAD).

APC p.Arg653=

c.1959G>A · rs72541809 · VCV133524

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 30 submitters

gnomAD v4.1

Rare

rare (popmax 0.374%, 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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.6	GERP 0.047, phastCons 1
Overall
CADD	13.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.374% European (non-Finnish) · 4,405/1,177,136 alleles

Filtering AF 0.365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.361%

Overall 0.423% 6,805/1,610,582 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.1%	32
European (non-Finnish)grpmax	0.374%	267
Remaining individualsnot grpmax-eligible	0.34%	294
Middle Eastern	0.182%	550
Admixed American	0.18%	555
Ashkenazi Jewishnot grpmax-eligible	0.101%	986
African / African-American	0.0761%	1,314
South Asian	0.0022%	45,459

Finnish 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.Arg653=
Coding: c.1959G>A
MANE Select: NM_000038
dbSNP: rs72541809
Type: single nucleotide variant
Location: chr5:112837553 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 653: an α-helix

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 classic familial adenomatous polyposis familial adenomatous polyposis 1

Similar variants

APC p.Arg653Gly Pathogenic ★★ same residue
APC p.Arg653Lys Pathogenic ★★ same residue
APC p.Arg653Met Pathogenic ★★ same residue
APC p.Arg653Thr 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

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-arg653 (accessed [today's date]).

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