Is APC p.Asp78Ala (c.233A>C) pathogenic?

APC p.Asp78Ala (c.233A>C) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.3125); Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Asp78Ala (c.233A>C)?

APC p.Asp78Ala (c.233A>C) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Asp78Ala (c.233A>C) in the general population?

APC p.Asp78Ala (c.233A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about APC p.Asp78Ala (c.233A>C)?

AlphaMissense predicts likely benign (score 0.3125) — an in-silico prediction, not a clinical call.

APC p.Asp78Ala

c.233A>C · rs562833260 · VCV482349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3125	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	24.0	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 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,856 alleles · very rare exomes 1/1,461,504 · genomes 1/152,352 · 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.Asp78Ala
Coding: c.233A>C
MANE Select: NM_000038
dbSNP: rs562833260
Type: single nucleotide variant
Location: chr5:112767201 (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

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Asp78Asn Uncertain significance ★★ ⚠ same residue
APC p.Asp78Glu Uncertain significance ★★ ⚠ same residue
APC p.Asp78His Uncertain significance ★★ same residue
APC p.Asp78= Likely benign ★ same residue
APC p.Asp78fs Pathogenic ★★ 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-asp78ala (accessed [today's date]).

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