Is APC p.Ala41= (c.123A>G) pathogenic?

APC p.Ala41= (c.123A>G) is classified Likely benign in APC (ClinVar, Expert panel, 5 submitters; last evaluated 2023-02-18). Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala41= (c.123A>G)?

APC p.Ala41= (c.123A>G) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala41= (c.123A>G) in the general population?

APC p.Ala41= (c.123A>G) 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.Ala41=

c.123A>G · rs1561445056 · VCV631238

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 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 Benign for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PM2_Supporting BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.123A>G (p.Ala41=) variant in APC is synonymous (silent) variant that is not predicted by SpliceAI and VarSEAK to impact splicing (BP4 and BP7 met). This variant is absent from gnomAD v2.1.1 (PM2_supporting). This variant has been observed in heterozygous state in 1 healthy adult individual worth 0.5 healthy individual points in total (BS2_supporting not met; Invitae internal data). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BP4, BP7 (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 carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.37, phastCons 1
Overall
CADD	12.6	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.Ala41=
Coding: c.123A>G
MANE Select: NM_000038
dbSNP: rs1561445056
Type: single nucleotide variant
Location: chr5:112755013 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 41: 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: 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.Ala41Val Uncertain significance ★★ ⚠ same residue
APC p.Ala41Glu Uncertain significance ★ same residue
APC p.Ala41Ser Uncertain significance ★ same residue
APC p.Ala41Thr Conflicting classifications of pathogenicity ★ same residue
APC p.Pro41= Uncertain significance ★ same residue
APC p.Pro41Ala Conflicting classifications of pathogenicity ★ same residue
APC p.Pro41Arg Uncertain significance ★ same residue
APC p.Pro41Ser Uncertain significance ★ same residue

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-ala41 (accessed [today's date]).

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