Is APC p.Ala426Ser (c.1276G>T) pathogenic?

APC p.Ala426Ser (c.1276G>T) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0711); Rare (popmax 0.1%, eas); Associated with Desmoid disease, hereditary.

What condition is associated with APC p.Ala426Ser (c.1276G>T)?

APC p.Ala426Ser (c.1276G>T) is associated with Desmoid disease, hereditary, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala426Ser (c.1276G>T) in the general population?

APC p.Ala426Ser (c.1276G>T) is rare (popmax 0.1%, eas) (gnomAD).

What do computational predictors say about APC p.Ala426Ser (c.1276G>T)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

APC p.Ala426Ser

c.1276G>T · rs200598389 · VCV230445

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Conditions

Desmoid disease, hereditary

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.336	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,173 bp · p 0.36 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% East Asian · 45/44,866 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00366% 59/1,614,012 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	997
South Asian	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0048%	20,832
European (non-Finnish)	0.000169%	589,981

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.Ala426Ser
Coding: c.1276G>T
MANE Select: NM_000038
dbSNP: rs200598389
Type: single nucleotide variant
Location: chr5:112819308 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 426: an α-helix

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

Disease context

Desmoid disease, hereditary — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1 classic or attenuated familial adenomatous polyposis

Similar variants

APC p.Ala426Asp Uncertain significance ★★ same residue
APC p.Ala426Thr Uncertain significance ★★ same residue
APC p.Ala426= Benign/Likely benign ★★ same residue
APC p.Ala426Val Uncertain significance ★ same residue
APC p.Ala426fs Pathogenic ★ same residue
APC p.Ala426_His427del Uncertain significance ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G 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-ala426ser (accessed [today's date]).

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