Is MID2 p.Arg223Cys (c.667C>T) pathogenic?

MID2 p.Arg223Cys (c.667C>T) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-12-01). AlphaMissense: ambiguous (0.4644); Very rare (popmax 0.00356%, sas).

How common is MID2 p.Arg223Cys (c.667C>T) in the general population?

MID2 p.Arg223Cys (c.667C>T) is very rare (popmax 0.00356%, sas) (gnomAD).

What do computational predictors say about MID2 p.Arg223Cys (c.667C>T)?

AlphaMissense predicts ambiguous (score 0.4644) — an in-silico prediction, not a clinical call.

MID2 p.Arg223Cys

c.667C>T · rs751834460 · VCV425513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, sas)

Computational evidence

Protein change
AlphaMissense	0.4644	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -6.15	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 101 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	25.3	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 0.00356% South Asian · 2/56,174 alleles

Filtering AF 0.00059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000221%

Overall 0.000498% 6/1,205,845 alleles · very rare exomes 5/1,095,015 · genomes 1/110,830 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00356%	28,087
European (non-Finnish)	0.000448%	223,265

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: MID2
Protein: p.Arg223Cys
Coding: c.667C>T
MANE Select: NM_012216
dbSNP: rs751834460
Type: single nucleotide variant
Location: chrX:107841332 (GRCh38)
Structure: AlphaFold pLDDT 80.18 · 4 PDB
Residue 223: a turn

Full MID2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MID2 p.Ala150Ser Uncertain significance ★★ ⚠ same type
MID2 p.Arg121His Uncertain significance ★★ ⚠ same type
MID2 p.Arg164Gly Uncertain significance ★★ ⚠ same type
MID2 p.Ser60= Benign ★★ same type
MID2 p.Thr194= Benign/Likely benign ★★ same type
MID2 p.Arg105Pro Uncertain significance ★ ⚠ same type
MID2 p.Arg121Cys Uncertain significance ★ ⚠ same type
MID2 p.Arg121Leu Uncertain significance ★ ⚠ 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/mid2-p-arg223cys (accessed [today's date]).

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