Is MIPEP p.Arg366Cys (c.1096C>T) pathogenic?

MIPEP p.Arg366Cys (c.1096C>T) is classified Uncertain significance in MIPEP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-01). AlphaMissense: ambiguous (0.4519); Ultra-rare (popmax 0.0658%, mid); Associated with Inborn genetic diseases.

What condition is associated with MIPEP p.Arg366Cys (c.1096C>T)?

MIPEP p.Arg366Cys (c.1096C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MIPEP p.Arg366Cys (c.1096C>T) in the general population?

MIPEP p.Arg366Cys (c.1096C>T) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about MIPEP p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts ambiguous (score 0.4519) — an in-silico prediction, not a clinical call.

MIPEP p.Arg366Cys

c.1096C>T · rs149545169 · VCV2071273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4519 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4519	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -10.36	damaging
Splicing
SpliceAI	Δ0.29	donor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 159 kb · p 0.25 · regional, not allelic
Overall
CADD	33.0	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 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00886% 143/1,613,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
Admixed American	0.0384%	2,607
African / African-American	0.0334%	2,992
Remaining individualsnot grpmax-eligible	0.0128%	7,807
European (non-Finnish)	0.00695%	14,384
South Asian	0.0011%	91,050

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: MIPEP
Protein: p.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_005932
dbSNP: rs149545169
Type: single nucleotide variant
Location: chr13:23858870 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.33

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MIPEP p.Arg366Gly Uncertain significance ★ ⚠ same residue
MIPEP p.Ala138Val Uncertain significance ★★ ⚠ same condition
MIPEP p.Arg453His Uncertain significance ★★ ⚠ same condition
MIPEP p.Arg509His Uncertain significance ★★ ⚠ same condition
MIPEP p.Arg560His Uncertain significance ★★ ⚠ same condition
MIPEP p.Arg621Gln Uncertain significance ★★ same condition
MIPEP p.Arg662Cys Uncertain significance ★★ ⚠ same condition
MIPEP p.Asp168Ala Uncertain significance ★★ ⚠ 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/mipep-p-arg366cys (accessed [today's date]).

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