Is APC p.Ala146= (c.438T>C) pathogenic?

APC p.Ala146= (c.438T>C) is classified Likely benign in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). Very rare (popmax 8.51e-05%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala146= (c.438T>C)?

APC p.Ala146= (c.438T>C) is associated with familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala146= (c.438T>C) in the general population?

APC p.Ala146= (c.438T>C) is very rare (popmax 8.51e-05%, nfe) (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.Ala146=

c.438T>C · rs2149614610 · VCV1107776

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

familial adenomatous polyposis 1

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 · T>A here scores Δ0.91 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.5	phastCons 1
Overall
CADD	10.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,992 alleles

Overall 6.23e-05% 1/1,604,476 alleles · very rare exomes 1/1,452,314 · genomes 0/152,162 · joint denominator

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.Ala146=
Coding: c.438T>C
MANE Select: NM_000038
dbSNP: rs2149614610
Type: single nucleotide variant
Location: chr5:112775644 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 146: 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

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.Ala146Gly Uncertain significance ★★ same residue
APC p.Ala146Ser Uncertain significance ★★ same residue
APC p.Ala146Thr Uncertain significance ★★ same residue
APC p.Ala146Val Uncertain significance ★★ same residue
APC p.Ala146Pro 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

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-ala146 (accessed [today's date]).

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