Is AIP p.Cys121Arg (c.361T>C) pathogenic?

AIP p.Cys121Arg (c.361T>C) is classified Uncertain significance in AIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely pathogenic (0.6198); Very rare (popmax 8.48e-05%, nfe).

How common is AIP p.Cys121Arg (c.361T>C) in the general population?

AIP p.Cys121Arg (c.361T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about AIP p.Cys121Arg (c.361T>C)?

AlphaMissense predicts likely pathogenic (score 0.6198) — an in-silico prediction, not a clinical call.

AIP p.Cys121Arg

c.361T>C · rs2495401755 · VCV2964224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6198 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6198	likely pathogenic
REVEL	0.698	pathogenic-leaning
SaProt	LLR -13.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP -1.7, phastCons 1
Overall
CADD	22.9	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 8.48e-05% European (non-Finnish) · 1/1,179,874 alleles

Overall 6.85e-05% 1/1,460,406 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: AIP
Protein: p.Cys121Arg
Coding: c.361T>C
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs2495401755
Type: single nucleotide variant
Location: chr11:67489348 (GRCh38)
Structure: AlphaFold pLDDT 70.14 · 81 PDB

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

Similar variants

AIP p.Cys121Phe Uncertain significance ★ ⚠ same residue
AIP p.Cys121= Likely benign ★ same residue
AIP p.Cys121fs Pathogenic ★ same residue
AIP p.Arg271Trp Pathogenic/Likely pathogenic ★★ same type
AIP p.Arg304Ter Pathogenic ★★ same type
AIP p.Arg81Ter Pathogenic ★★ same type
AIP p.Cys238Tyr Likely pathogenic ★★ same type
AIP p.Gln126Ter 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/aip-p-cys121arg (accessed [today's date]).

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