Is AIP p.Arg56Cys (c.166C>T) pathogenic?

AIP p.Arg56Cys (c.166C>T) is classified Uncertain significance in AIP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-17). AlphaMissense: likely benign (0.1392); Very rare (popmax 0.004%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with AIP p.Arg56Cys (c.166C>T)?

AIP p.Arg56Cys (c.166C>T) is associated with hereditary neoplastic syndrome, growth hormone secreting pituitary adenoma 1 (ClinVar).

How common is AIP p.Arg56Cys (c.166C>T) in the general population?

AIP p.Arg56Cys (c.166C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about AIP p.Arg56Cys (c.166C>T)?

AlphaMissense predicts likely benign (score 0.1392) — an in-silico prediction, not a clinical call.

AIP p.Arg56Cys

c.166C>T · rs267606538 · VCV877266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1392 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1392	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -2.1, phastCons 0.5
Overall
CADD	18.22	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000744% 12/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,974
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000678%	147,507

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: AIP
Protein: p.Arg56Cys
Coding: c.166C>T
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs267606538
Type: single nucleotide variant
Location: chr11:67487072 (GRCh38)
Structure: AlphaFold pLDDT 70.14 · 81 PDB

Full AIP 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: growth hormone secreting pituitary adenoma 1

Similar variants

AIP p.Arg56Pro Uncertain significance ★★ ⚠ same residue
AIP p.Arg56Leu Uncertain significance ★ ⚠ same residue
AURKAIP1 p.Ala56Ser Uncertain significance ★ ⚠ same residue
AIP p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
AIP p.Arg304Ter Pathogenic ★★ same condition
AIP p.Arg81Ter Pathogenic ★★ same condition
AIP p.Cys238Tyr Likely pathogenic ★★ same condition
AIP p.Gln126Ter 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/aip-p-arg56cys (accessed [today's date]).

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