Is APC p.Pro1140Arg (c.3419C>G) pathogenic?

APC p.Pro1140Arg (c.3419C>G) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-11). AlphaMissense: likely pathogenic (0.7253); Very rare (popmax 0.00329%, sas); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.Pro1140Arg (c.3419C>G)?

APC p.Pro1140Arg (c.3419C>G) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro1140Arg (c.3419C>G) in the general population?

APC p.Pro1140Arg (c.3419C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about APC p.Pro1140Arg (c.3419C>G)?

AlphaMissense predicts likely pathogenic (score 0.7253) — an in-silico prediction, not a clinical call.

APC p.Pro1140Arg

c.3419C>G · rs1060503351 · VCV411525

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.7253	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
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	25.6	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

Grpmax group 0.00329% South Asian · 3/91,072 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000682% 11/1,613,820 alleles · very rare exomes 9/1,461,810 · genomes 2/152,010 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,357
African / African-American	0.00267%	37,419
Admixed American	0.00167%	59,980
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000339%	295,001

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.Pro1140Arg
Coding: c.3419C>G
MANE Select: NM_000038
dbSNP: rs1060503351
Type: single nucleotide variant
Location: chr5:112839013 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1140: the 'responsible for down-regulation through a process mediated by direct ubiquitination' region; the 'interaction with catenins' region; the 'disordered' region

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

Disease context

classic or attenuated familial adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Pro1140Ala Uncertain significance ★★ same residue
APC p.Pro1140= Likely benign ★★ same residue
APC p.Pro1140Leu Uncertain significance ★ ⚠ same residue
APC p.Pro1140Ser 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
APC c.1312+5G>C 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-pro1140arg (accessed [today's date]).

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