Is APC p.Ala735Ser (c.2203G>T) pathogenic?

APC p.Ala735Ser (c.2203G>T) is classified Uncertain significance in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely benign (0.0964); Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala735Ser (c.2203G>T)?

APC p.Ala735Ser (c.2203G>T) is associated with familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala735Ser (c.2203G>T) in the general population?

APC p.Ala735Ser (c.2203G>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.

What do computational predictors say about APC p.Ala735Ser (c.2203G>T)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

APC p.Ala735Ser

c.2203G>T · rs559313229 · VCV2771975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.12	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 256 bp · p 0.22 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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.Ala735Ser
Coding: c.2203G>T
MANE Select: NM_000038
dbSNP: rs559313229
Type: single nucleotide variant
Location: chr5:112837797 (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

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.Ala735Thr Uncertain significance ★★ ⚠ same residue
APC p.Ala735Val Benign/Likely benign ★★ same residue
APC p.Ala735= Conflicting classifications of pathogenicity ★ same residue
APC p.Ala735Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
APC p.Ala735fs Pathogenic ★ same residue
APC p.Ala735_Lys736insAla Uncertain significance ★ same residue
APC p.Ala735Glu 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-ala735ser (accessed [today's date]).

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