Is APC p.Ala612Val (c.1835C>T) pathogenic?

APC p.Ala612Val (c.1835C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.8909); Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala612Val (c.1835C>T)?

APC p.Ala612Val (c.1835C>T) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala612Val (c.1835C>T) in the general population?

APC p.Ala612Val (c.1835C>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.Ala612Val (c.1835C>T)?

AlphaMissense predicts likely pathogenic (score 0.8909) — an in-silico prediction, not a clinical call.

APC p.Ala612Val

c.1835C>T · rs1580603927 · VCV820149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8909 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.8909	likely pathogenic
REVEL	0.562	indeterminate
SaProt	—	not scored · why
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	26.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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.Ala612Val
Coding: c.1835C>T
MANE Select: NM_000038
dbSNP: rs1580603927
Type: single nucleotide variant
Location: chr5:112835042 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 612: 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.Ala612Gly Uncertain significance ★★ same residue
APC p.Ala612Ser Uncertain significance ★★ same residue
APC p.Ala612Thr Uncertain significance ★★ same residue
APC p.Ala612= Benign/Likely benign ★★ same residue
APC p.Ala612Pro 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-ala612val (accessed [today's date]).

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