Is APC p.His652= (c.1956C>T) pathogenic?

APC p.His652= (c.1956C>T) is classified Likely pathogenic in APC (ClinVar, Expert panel, 6 submitters; last evaluated 2023-02-25). Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.His652= (c.1956C>T)?

APC p.His652= (c.1956C>T) is associated with familial adenomatous polyposis 1, colon carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is APC p.His652= (c.1956C>T) in the general population?

APC p.His652= (c.1956C>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial adenomatous polyposis inherited?

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

APC p.His652=

c.1956C>T · rs1064793716 · VCV419202

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Likely Pathogenic for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PM2_Supporting PS4_Supporting PS3

Curation rationale (ClinGen, verbatim)

The c.1956C>T variant in APC is predicted to be a synonymous (silent) variant (p.His652=). It is located at the third-last nucleotide of exon 15. Two RNA based RT-PCR assays demonstrate out-of-frame skipping of exon 15, with evidence that the variant allele produces <10% of the full-length transcript (PS3; PMID: 15459959, 22987206). This variant has been reported in 3 probands meeting least 1.5 phenotype points (PS4_Supporting; PMID: 15459959, 22987206). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 1.1, phastCons 1
Overall
CADD	17.85	PHRED · no single calibrated threshold — expert panels disagree

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.His652=
Coding: c.1956C>T
MANE Select: NM_000038
dbSNP: rs1064793716
Type: single nucleotide variant
Location: chr5:112835163 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 652: an α-helix

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

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colon carcinoma hereditary neoplastic syndrome

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.His652Gln Uncertain significance ★★ same residue
APC p.His652Pro Uncertain significance ★★ ⚠ same residue
APC p.His652Arg Uncertain significance ★ ⚠ same residue
APC p.His652Asn Uncertain significance ★ 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-his652 (accessed [today's date]).

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