Is APC p.Ala604Val (c.1811C>T) pathogenic?

APC p.Ala604Val (c.1811C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.2504); Very rare (popmax 8.47e-05%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala604Val (c.1811C>T)?

APC p.Ala604Val (c.1811C>T) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala604Val (c.1811C>T) in the general population?

APC p.Ala604Val (c.1811C>T) is very rare (popmax 8.47e-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.

What do computational predictors say about APC p.Ala604Val (c.1811C>T)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

APC p.Ala604Val

c.1811C>T · rs370955311 · VCV490227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign
REVEL	0.248	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.5	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,992 alleles

Overall 6.2e-05% 1/1,614,086 alleles · very rare exomes 1/1,461,828 · genomes 0/152,258 · 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.Ala604Val
Coding: c.1811C>T
MANE Select: NM_000038
dbSNP: rs370955311
Type: single nucleotide variant
Location: chr5:112835018 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 604: 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.Ala604Ser Uncertain significance ★★ same residue
APC p.Ala604Thr Uncertain significance ★★ same residue
APC p.Ala604Gly Conflicting classifications of pathogenicity ★ same residue
APC p.Ala604Pro Uncertain significance ★ same residue
APC p.Ala604= Likely benign ★ same residue
APC p.Ala604_Asp605insTer Pathogenic ★★ 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-ala604val (accessed [today's date]).

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