Is MID2 p.Arg121Cys (c.361C>T) pathogenic?

MID2 p.Arg121Cys (c.361C>T) is classified Uncertain significance in MID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.226); Ultra-rare (popmax 0.0423%, sas).

How common is MID2 p.Arg121Cys (c.361C>T) in the general population?

MID2 p.Arg121Cys (c.361C>T) is ultra-rare (popmax 0.0423%, sas) (gnomAD).

What do computational predictors say about MID2 p.Arg121Cys (c.361C>T)?

AlphaMissense predicts likely benign (score 0.226) — an in-silico prediction, not a clinical call.

MID2 p.Arg121Cys

c.361C>T · rs779067600 · VCV3126344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.226 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.226	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 101 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0423% South Asian · 24/56,721 alleles

Filtering AF 0.0291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00265% 32/1,209,241 alleles · ultra-rare exomes 31/1,098,048 · genomes 1/111,193 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0423%	2,363
Middle Eastern	0.0229%	4,372
Admixed American	0.00219%	45,745
African / African-American	0.00176%	56,870
European (non-Finnish)	0.000559%	179,000

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.Arg121Cys
Coding: c.361C>T
MANE Select: NM_012216
dbSNP: rs779067600
Type: single nucleotide variant
Location: chrX:107841026 (GRCh38)
Structure: AlphaFold pLDDT 80.18 · 4 PDB

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

Similar variants

MID2 p.Arg121His Uncertain significance ★★ ⚠ same residue
MID2 p.Arg121Leu Uncertain significance ★ ⚠ same residue
MID2 p.Ala150Ser 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.Arg122Gln 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-arg121cys (accessed [today's date]).

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