Is APC p.Arg71His (c.212G>A) pathogenic?

APC p.Arg71His (c.212G>A) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1581); Very rare (popmax 0.00894%, eas); Associated with colorectal cancer.

What condition is associated with APC p.Arg71His (c.212G>A)?

APC p.Arg71His (c.212G>A) is associated with colorectal cancer, gastric cancer, hepatocellular carcinoma (ClinVar).

How common is APC p.Arg71His (c.212G>A) in the general population?

APC p.Arg71His (c.212G>A) is very rare (popmax 0.00894%, eas) (gnomAD).

What do computational predictors say about APC p.Arg71His (c.212G>A)?

AlphaMissense predicts likely benign (score 0.1581) — an in-silico prediction, not a clinical call.

APC p.Arg71His

c.212G>A · rs750503329 · VCV411444

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00894%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.1581	likely benign
REVEL	0.199	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	32.0	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 0.00894% East Asian · 4/44,718 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000995% 16/1,607,242 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00894%	11,180
Remaining individualsnot grpmax-eligible	0.00161%	62,252
Finnishnot grpmax-eligible	0.00156%	63,984
African / African-American	0.00134%	74,750
European (non-Finnish)	0.000766%	130,464

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.Arg71His
Coding: c.212G>A
MANE Select: NM_000038
dbSNP: rs750503329
Type: single nucleotide variant
Location: chr5:112766402 (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

colorectal cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer hepatocellular carcinoma hereditary neoplastic syndrome gastric adenocarcinoma and proximal polyposis of the stomach familial adenomatous polyposis 1 classic or attenuated familial adenomatous polyposis

Similar variants

APC p.Arg71Cys Uncertain significance ★★ same residue
APC p.Arg71Leu Uncertain significance ★★ same residue
APC p.Arg71Pro Uncertain significance ★★ same residue
APC p.Arg71Ser Uncertain significance ★★ ⚠ same residue
APC p.Arg71= Likely benign ★ same residue
APC p.Arg71fs Pathogenic ★ 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-arg71his (accessed [today's date]).

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