Is APC p.Ala735= (c.2205G>A) pathogenic?

APC p.Ala735= (c.2205G>A) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0489%, nfe); Associated with APC-Associated Polyposis Disorders.

What condition is associated with APC p.Ala735= (c.2205G>A)?

APC p.Ala735= (c.2205G>A) is associated with APC-Associated Polyposis Disorders, colon carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala735= (c.2205G>A) in the general population?

APC p.Ala735= (c.2205G>A) is ultra-rare (popmax 0.0489%, nfe) (gnomAD).

APC p.Ala735=

c.2205G>A · rs141001261 · VCV183919

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0489%, nfe)

Conditions

APC-Associated Polyposis Disorders

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 -0.021	GERP -2.3, phastCons 0.014
Overall
CADD	8.135	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0489% European (non-Finnish) · 577/1,180,016 alleles

Filtering AF 0.0456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0443%

Overall 0.0367% 593/1,613,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0489%	2,045
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00934%	10,702
Admixed American	0.00167%	59,978

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.Ala735=
Coding: c.2205G>A
MANE Select: NM_000038
dbSNP: rs141001261
Type: single nucleotide variant
Location: chr5:112837799 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 735: an α-helix

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

Disease context

APC-Associated Polyposis Disorders

Also linked: colon carcinoma hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Ala735Glu Uncertain significance ★★ same residue
APC p.Ala735Thr Uncertain significance ★★ ⚠ same residue
APC p.Ala735Val Benign/Likely benign ★★ same residue
APC p.Ala735Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
APC p.Ala735Ser Uncertain significance ★ ⚠ same residue
APC p.Ala735fs Pathogenic ★ same residue
APC p.Ala735_Lys736insAla Uncertain significance ★ same residue
APC c.1312+3A>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-ala735 (accessed [today's date]).

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