Is APC p.Arg348Gln (c.1043G>A) pathogenic?

APC p.Arg348Gln (c.1043G>A) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-04). AlphaMissense: likely pathogenic (0.9753); Very rare (popmax 0.00167%, amr); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg348Gln (c.1043G>A)?

APC p.Arg348Gln (c.1043G>A) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Arg348Gln (c.1043G>A) in the general population?

APC p.Arg348Gln (c.1043G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Familial adenomatous polyposis inherited?

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

What do computational predictors say about APC p.Arg348Gln (c.1043G>A)?

AlphaMissense predicts likely pathogenic (score 0.9753) — an in-silico prediction, not a clinical call.

APC p.Arg348Gln

c.1043G>A · rs1402950946 · VCV482287

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.9753	likely pathogenic · top 10% in APC
REVEL	0.765	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,173 bp · p 0.36 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,994 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,824 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,994
European (non-Finnish)	0.000508%	196,667

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.Arg348Gln
Coding: c.1043G>A
MANE Select: NM_000038
dbSNP: rs1402950946
Type: single nucleotide variant
Location: chr5:112819075 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 348: 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.Arg348Ter Uncertain significance ★★★ same residue
APC p.Arg348= Benign/Likely benign ★★ same residue
APC p.Arg348Leu Uncertain significance ★ ⚠ same residue
APC p.Arg348fs 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-arg348gln (accessed [today's date]).

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