Is APC p.Ala59Val (c.176C>T) pathogenic?

APC p.Ala59Val (c.176C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-30). AlphaMissense: likely benign (0.1637); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Ala59Val (c.176C>T)?

APC p.Ala59Val (c.176C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala59Val (c.176C>T) in the general population?

APC p.Ala59Val (c.176C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APC p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely benign (score 0.1637) — an in-silico prediction, not a clinical call.

APC p.Ala59Val

c.176C>T · rs2149784325 · VCV1779767

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1637 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1637	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	22.3	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

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.Ala59Val
Coding: c.176C>T
MANE Select: NM_000038
dbSNP: rs2149784325
Type: single nucleotide variant
Location: chr5:112766366 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Disease context

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

Similar variants

APC p.Ala59Gly Uncertain significance ★★ ⚠ same residue
APC p.Ala59Pro Uncertain significance ★★ same residue
APC p.Ala59Thr Uncertain significance ★★ ⚠ same residue
APC p.Ala59= Benign/Likely benign ★★ same residue
APC p.Ala59Ser 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-ala59val (accessed [today's date]).

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