Is APC p.Pro981Ser (c.2941C>T) pathogenic?

APC p.Pro981Ser (c.2941C>T) is classified Uncertain significance in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-26). AlphaMissense: likely pathogenic (0.671); Very rare (popmax 0.00223%, eas).

How common is APC p.Pro981Ser (c.2941C>T) in the general population?

APC p.Pro981Ser (c.2941C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about APC p.Pro981Ser (c.2941C>T)?

AlphaMissense predicts likely pathogenic (score 0.671) — an in-silico prediction, not a clinical call.

APC p.Pro981Ser

c.2941C>T · rs2149880710 · VCV1337327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.671	likely pathogenic
REVEL	0.668	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 6.84e-05% 1/1,461,868 alleles · very rare

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.Pro981Ser
Coding: c.2941C>T
MANE Select: NM_000038
dbSNP: rs2149880710
Type: single nucleotide variant
Location: chr5:112838535 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 981: the 'disordered' region; the 'responsible for down-regulation through a process mediated by direct ubiquitination' region

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

Similar variants

APC p.Pro981Arg Uncertain significance ★★ ⚠ same residue
APC p.Pro981Leu Uncertain significance ★ ⚠ same residue
APC p.Pro981= Benign ★ same residue
APC p.Pro981_Ser982insTer Pathogenic ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same type
APC c.1312+3A>G Pathogenic ★★★ same type
APC c.1312+5G>A Likely pathogenic ★★★ same type
APC c.1312+5G>C Likely pathogenic ★★★ same type

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-pro981ser (accessed [today's date]).

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