Is APC p.His2149Pro (c.6446A>C) pathogenic?

APC p.His2149Pro (c.6446A>C) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2025-10-31). AlphaMissense: likely pathogenic (0.6376); Very rare (popmax 0.00237%, nfe); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.His2149Pro (c.6446A>C)?

APC p.His2149Pro (c.6446A>C) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.His2149Pro (c.6446A>C) in the general population?

APC p.His2149Pro (c.6446A>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about APC p.His2149Pro (c.6446A>C)?

AlphaMissense predicts likely pathogenic (score 0.6376) — an in-silico prediction, not a clinical call.

APC p.His2149Pro

c.6446A>C · rs749230730 · VCV185017

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.6376 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.6376	likely pathogenic
REVEL	0.802	moderately 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 11	GERP 2.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	25.0	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 0.00237% European (non-Finnish) · 28/1,179,372 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00174% 28/1,613,294 alleles · very rare exomes 26/1,461,118 · genomes 2/152,176 · 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.His2149Pro
Coding: c.6446A>C
MANE Select: NM_000038
dbSNP: rs749230730
Type: single nucleotide variant
Location: chr5:112842040 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2149: 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.His2149Arg Uncertain significance ★★ same residue
APC p.His2149= Benign/Likely benign ★★ same residue
APC p.His2149Asp Uncertain significance ★ same residue
APC p.His2149Leu Uncertain significance ★ same residue
APC p.His2149Tyr Uncertain significance ★ same residue
APC p.His2149del Uncertain significance ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G 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-his2149pro (accessed [today's date]).

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