Is APC p.Arg653Lys (c.1958G>A) pathogenic?

APC p.Arg653Lys (c.1958G>A) is classified Pathogenic in APC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-14). AlphaMissense: likely pathogenic (0.9537); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Arg653Lys (c.1958G>A)?

APC p.Arg653Lys (c.1958G>A) is associated with hereditary neoplastic syndrome, colon carcinoma, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg653Lys (c.1958G>A) in the general population?

APC p.Arg653Lys (c.1958G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APC p.Arg653Lys (c.1958G>A)?

AlphaMissense predicts likely pathogenic (score 0.9537) — an in-silico prediction, not a clinical call.

APC p.Arg653Lys

c.1958G>A · rs1060503318 · VCV428128

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9537 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9537	likely pathogenic ✓ concordant with ClinVar
REVEL	0.748	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.73	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APC
Protein: p.Arg653Lys
Coding: c.1958G>A
MANE Select: NM_000038
dbSNP: rs1060503318
Type: single nucleotide variant
Location: chr5:112835165 (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

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

Also linked: colon carcinoma familial adenomatous polyposis 1

Similar variants

APC p.Arg653Gly Pathogenic ★★ same residue
APC p.Arg653Met Pathogenic ★★ same residue
APC p.Arg653= Benign/Likely benign ★★ 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-arg653lys (accessed [today's date]).

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